Asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680

Article abstract of DOI:10.1016/j.tetasy.2017.09.022

The asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680 are reported. Conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to the requisite (E)-α,β-unsaturated ester followed by in situ enolate oxidation with (?)-(camphorsulfonyl)oxaziridne (CSO) gave the corresponding anti-α-hydroxy-β-amino esters. Sequential Swern oxidation followed by diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino esters. Subsequent N-debenzylation (i.e., hydrogenolysis for microginin 612, and NaBrO₃-mediated oxidative N-debenzylation for microginins 646 and 680) followed by acid catalysed ester hydrolysis gave the corresponding syn-α-hydroxy-β-amino acids, the N-terminal components of microginins 612, 646 and 680, in good yield. An analogous strategy for elaboration of the enantiopure anti-α-hydroxy-β-amino esters facilitated the asymmetric synthesis of the corresponding C(2)-epimeric α-hydroxy-β-amino acids.

Full text of DOI:10.1016/j.tetasy.2017.09.022

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric syntheses of the N-terminal
a
-hydroxy-b-amino acid
components of microginins 612, 646 and 680
⇑
Stephen G. Davies , Ai M. Fletcher, Abigail R. Hanby, Paul M. Roberts, James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric syntheses of the N-terminal
646 and 680 are reported. Conjugate addition of lithium (R)-N-benzyl-N-(
a
-hydroxy-b-amino acid components of microginins 612,
-methylbenzyl)amide to the
,b-unsaturated ester followed by in situ enolate oxidation with (ꢀ)-(camphorsulfonyl)ox-
aziridne (CSO) gave the corresponding anti- -hydroxy-b-amino esters. Sequential Swern oxidation fol-
lowed by diastereoselective reduction gave the corresponding syn- -hydroxy-b-amino esters.
Received 8 September 2017
Accepted 26 September 2017
Available online xxxx
a
requisite (E)-
a
a
a
Subsequent N-debenzylation (i.e., hydrogenolysis for microginin 612, and NaBrO3-mediated oxidative
N-debenzylation for microginins 646 and 680) followed by acid catalysed ester hydrolysis gave the cor-
responding syn-
in good yield. An analogous strategy for elaboration of the enantiopure anti-
facilitated the asymmetric synthesis of the corresponding C(2)-epimeric -hydroxy-b-amino acids.
a-hydroxy-b-amino acids, the N-terminal components of microginins 612, 646 and 680,
a
-hydroxy-b-amino esters
a
Ó 2017 Published by Elsevier Ltd.
1. Introduction
anti-
a-hydroxy-b-amino ester 10 in 63% yield and >99:1 dr.
Catalytic hydrogenolysis of 10 gave amine 11, and subsequent
acid-mediated ester hydrolysis gave (2R,3R)-3-amino-2-hydroxy-
decanoic acid 13 in 59% yield (from 10). The corresponding C(2)-
epimer 15 was accessed via cyclisation of the corresponding
benzamide 12 under Mitsunobu conditions to give oxazoline 14
and global hydrolysis of 14 with 6.0 M HCl furnished (2S,3R)-3-
amino-2-hydroxydecanoic acid 15 in 64% yield (from 12).
Accordingly, it was anticipated that the asymmetric syntheses of
The microginins are a sub-class of linear peptides that have
been isolated from a genus of cyanobacteria known as Microcystis.1
Microginins typically contain between four to six amino acids (e.g.,
microginin 478 12 and microginin 299-C 23) and are characterised
by a functionalised b-amino acid at the N-terminus as well as the
presence of tyrosine residues. Microginin FR1 3 (often simply
called ‘‘microginin”) was the first in this class to be isolated from
the blue-green alga Microcystis aeruginosa.4 In 2016, three new
microginins, viz. microginin 612 4, microginin 646 5 and microgi-
nin 680 6, were isolated from Microcystis aeruginosa UTEX LB2386.5
Microginin 612 4 contains a rare amino acid residue, 3-amino-2-
hydroxyoctanoic acid (ahoa)6 and microginin 646 5 and microginin
680 6 are the first chlorinated examples of the ahoa fragment in a
natural product (Fig. 1).
syn-a-hydroxy-b-amino acids, the N-terminal components of
microginin 612 4, microginin 646 5 and microginin 680 6, and
the corresponding C(2)-epimers 19–21 could be achieved via
diastereoselective aminohydroxylation of the requisite
rated ester as the key step (Scheme 1).
a,b-unsatu-
2. Results and discussion
We have previously synthesised both diastereoisomers of 3-
amino-2-hydroxydecanoic acid (ahda), 13 and 15, as part of the
structural elucidation of microginin FR1 3, and concluded the
unknown N-terminal amino acid component of microginin FR1 3
was (2S,3R)-syn-ahda 15 by spectroscopic comparison.7 Diastere-
The requisite
a,b-unsaturated esters 23, 25 and 29 were pre-
pared from the corresponding aldehydes via olefination methodol-
ogy. Hexanal 22 and 6-chlorohexanal (which was prepared from 6-
chlorohexan-ol 24 by treatment with IBX) were treated with ylid
oselective conjugate addition of lithium (R)-N-benzyl-N-(
a-
30 to give the corresponding
a,b-unsaturated esters 23 and 25,
methylbenzyl)amide (R)-8 to ,b-unsaturated ester 7 followed by
a
respectively in 98:2 dr [(E):(Z)] in each case. Purification via flash
column chromatography afforded 23 and 25 in 87 and 83% isolated
yield, respectively, and >99:1 dr [(E):(Z)] in each case. Ozonolysis of
cyclohexene 26 gave dialdehyde 27, which was subsequently trea-
in situ enolate oxidation with (+)-CSO 9 gave the corresponding
⇑
Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
ted with 30 (1.0 equiv) to give
a,b-unsaturated ester 28 in 66%
https://doi.org/10.1016/j.tetasy.2017.09.022
0957-4166/Ó 2017 Published by Elsevier Ltd.
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2
S. G. Davies et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Ar
O
hydrolysis and purification via ion exchange chromatography gave
(2S,3R)-2-hydroxy-3-aminooctanoic acid [(2S,3R)-ahoa] 16 in 79%
yield and >99:1 dr (Scheme 4).
Hydrogenolytic N-debenzylation was attempted for chlorinated
b-amino esters 33, 34, 39 and 40. However, a significant amount of
competitive de-chlorination was observed under various
hydrogenolysis conditions.13 We have recently employed NaBrO3
and Na2S2O4 under biphasic conditions (EtOAc and H2O)14 as an
alternative, oxidative method for the N-debenzylation of tertiary
NH2
O
O
Me
N
H
N
CO2H
Ar
ClC7H14
N
H
N
Me
OH
O
microginin 478 1
Ar
O
NH2
O
O
Me
N
N
C7H15
N
H
N
Me
a-amino esters in the synthesis of anti-b-fluorophenylalanines,
OH
O
NH
Ar
where standard hydrogenolytic N-debenzylation conditions also
resulted in de-halogenation of the benzylic fluoride substrates.15
Treatment of 33 under these conditions resulted in the formation
of a complex mixture. The free hydroxyl group within 33 was
therefore protected by derivatisation to the corresponding O-acet-
ate upon treatment with Ac2O, which gave 43 in 93% yield. Treat-
ment of 43 with NaBrO3/Na2S2O4 promoted complete N-
debenzylation to give initially 44. Upon purification of the crude
sample of 44 by flash column chromatography on silica gel, migra-
tion of the O-acetyl group to the amino moiety was observed, giv-
ing 45 in 79% yield (from 43) and >99:1 dr. Global hydrolysis of the
amide and tert-butyl ester groups within 45 using 6.0 M aq HCl at
100 °C for 3 h followed by purification via ion-exchange chro-
matography gave (R,R)-2-hydroxy-3-amino-8-chlorooctanoic acid
[(R,R)-chloro-ahoa] 20 in 91% yield and >99:1 dr. Treatment of
the syn-analogue 39 with Ac2O in pyridine gave 46 in 89% yield,
and NaBrO3 mediated oxidative N-debenzylation of 46 followed
by ester hydrolysis gave (2S,3R)-2-hydroxy-3-amino-8-chlorooc-
tanoic acid [(2S,3R)-chloro-ahoa] 17 in 89% yield (from 46) and
>99:1 dr, after purification via ion-exchange chromatography
(Scheme 5).
O
microginin 299-C 2
CO2H
Ar
O
NH2
O
Me
O
H
N
H
N
CO2H
C7H15
N
H
N
Me
OH
O
Ar
microginin FR1 3
Ar
NH2
O
O
CO2H
Me
N
R2
N
H
N
R1
OH
O
Microginin 612 4: R1 = R2= H
Ar
Microginin 646 5: R1 = Cl, R2 = H
Microginin 680 6: R1 = R2= Cl
Figure 1. Examples of microginins 1–3 and the structures of microginin 612 4,
microginin 646 5 and microginin 680 6. [Ar = p-(HO)C6H4].
yield and >99:1 dr [(E):(Z)], in addition to diester 31 (ꢁ20%), which
The same deprotection protocol was applied to dichloro-ana-
logues 34 and 40. Treatment of 34 with Ac2O in pyridine gave 48
could easily be separated via flash column chromatography. Treat-
ment of 28 with ClPPh2 and NCS8 gave dichloroalkyl substituted
b-unsaturated ester 29 in 48% yield (Scheme 2).
a,
Ph
Conjugate addition of lithium amide (R)-8 to
ester 23 (R1 = R2 = H) followed by in situ enolate oxidation with
-hydroxy-b-amino ester 32 as a single
a,b-unsaturated
Ph
Ph
(R)-8
(i)
N
Li
Ph
N
(ꢀ)-CSO 9 gave anti-
a
CO2tBu
CO2tBu
C7H15
diastereoisomer (>99:1 dr) in 84% isolated yield. Similarly, treat-
C7H15
ment of 25 (R1 = Cl, R2 = H) and 29 (R1 = R2 = Cl)9 with (R)-8 fol-
7
OH
10, 63%, >99:1 dr
lowed by (ꢀ)-CSO 9 afforded anti-
a-hydroxy-b-amino esters 33
and 34 in 80 and 60% yield, respectively, and >99:1 dr in each case.
The relative configurations within 32–34 were assigned based on
the well-established stereochemical outcome of this anti-aminohy-
N
(ii)
S
O
O
(+)-9
O
Ph
droxylation process.10,11 The corresponding syn-
esters 38–40 were then prepared from anti-
a-hydroxy-b-amino
NHR
CO2tBu
(iv)
[R = Bz]
N
O
a-hydroxy-b-amino
C7H15
esters 32–34.12 Swern oxidation of 32 resulted in 100% conversion
to the corresponding ketone 35, and treatment of 35 with NaBH4 at
ꢀ20 °C gave an 85:15 mixture of syn-38 and anti-32, respectively.
Purification via flash column chromatography gave syn-38 as a
single diastereoisomer (>99:1 dr) in 57% yield. The same protocol
was applied for the preparation of syn-39 and syn-40. Swern
oxidation of 33 and 34 promoted 100% conversion to the
corresponding ketones 36 and 37, and subsequent reduction with
NaBH4 gave a 93:7 mixture of syn-39 and anti-33, and a 95:5
mixture of syn-40 and anti-34, respectively. Purification via column
chromatography gave syn-39 and syn-40 in 61 and 60% yield,
respectively, and >99:1 dr in each case (Scheme 3).
OH
C7H15
CO2tBu
11, R = H, 91%
12, R = Bz, 83%
(iii)
14, 84%, >99:1 dr
(vi)
[R = H]
(v)
NH2
NH2
CO2H
CO2H
C7H15
C7H15
OH
15, 92%
OH
13, 59%
NH2
NH2
R1
CO2H
R1
CO2H
Hydrogenolysis of 32 in the presence of Pd(OH)2/C (25% w/w)
under H2 (1 atm) afforded anti-a-hydroxy-b-amino ester 41 in
96% yield. Subsequent ester hydrolysis using 6.0 M aq HCl followed
by purification on Dowex 50WX8-200 ion exchange resin gave (R,
R)-2-hydroxy-3-aminooctanoic acid [(R,R)-ahoa] 19 in 60% yield
and >99:1 dr. Similarly, hydrogenolytic N-debenzylation of 38
R2
OH
R2
OH
16: R1 = H, R2 = H
17: R1 = Cl, R2 =H
18: R1 = Cl, R2 = Cl
19: R1 = H, R2 = H
20: R1 = Cl, R2 =H
21: R1 = Cl, R2 = Cl
Scheme 1. Reagents and conditions: (i) (R)-8, THF, ꢀ78 °C, 2 h, then (+)-CSO 9, rt,
16 h; (ii) H2, Pd/C, AcOH, rt, 16 h; (iii) PhCOCl, Et3N, CH2Cl2, 0 °C, 10 min then rt, 6 h;
(iv) DEAD, Ph3P, THF, rt, 26 h; (v) 6.0 M aq HCl,
using Pd(OH)2/C (25% w/w) under H2 (1 atm) gave syn-
a-
D, 7 h then Dowex; (vi) TFA, rt,
hydroxy-b-amino ester 42 in 91% yield. Acid-mediated ester
overnight then 1.0 M aq HCl, Dowex.
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S. G. Davies et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
(i)
Ph
CO2tBu
O
NH2
98:2 dr [(E):(Z)]
Ph
N
(i)
22
23, 87%, >99:1 dr [(E):(Z)]
CO2tBu
CO2tBu
OH
(ii), (iii)
Cl
OH
Cl
H
CO2tBu
25, 83%, >99:1 dr [(E):(Z)]
OH
32
41, 96%, >99:1 dr
98:2 dr [(E):(Z)]
24
(ii)
NH2
O
CO2tBu
(v)
H
(iv)
H
CO2H
O
O
OH
28, 66%, >99:1 dr [(E):(Z)]
26
27
19, 60%, >99:1 dr
(vi)
Ph
CO2tBu
Ph3P
NH2
(i)
Ph
N
CO2tBu
30
31
CO2tBu
Cl
CO2tBu
CO2tBu
tBuO2C
OH
Cl
OH
29
, 48%, >99:1 dr [(E):(Z)]
38
42, 91%, >99:1 dr
Scheme 2. Reagents and conditions: (i) 30, CH2Cl2, rt, 48 h; (ii) IBX, EtOAc, 70 °C,
24 h; (iii) 30, EtOAc, rt, 18 h; (iv) O3, CH2Cl2, ꢀ78 °C, 50 min then PPh3, ꢀ 78 °C to
0 °C, 4 h; (v) 30, CH2Cl2, rt, 18 h; (vi) NCS, ClPPh2, CH2Cl2, rt, 4 h.
(ii)
NH2
CO2H
in 98% yield. N-Debenzylation of 48 using NaBrO3/Na2S2O4 pro-
moted 100% conversion to 49, and subsequent acid mediated
hydrolysis at 100 °C gave a mixture of products including 21. The
by-products in this sample were tentatively assigned as a ꢁ2:1
mixture of (Z)-50 (3J7,8 = 7.0 Hz) and (E)-51 (3J7,8 = 13.2 Hz) based
upon 1H NMR spectroscopic and mass spectrometric analyses.
However, hydrolysis of the crude sample of 49 with 6.0 M HCl at
rt for 16 h followed by purification via ion-exchange chromatogra-
phy afforded (R,R)-2-hydroxy-3-amino-8,8-dichlorooctanoic acid
[(R,R)-dichloro-ahoa] 21 as a single diastereoisomer in 47% yield.
Treatment of syn-dichloro compound 40 with Ac2O gave 52 in
92% yield. N-Debenzylation of 52 with NaBrO3/Na2S2O4 followed
by hydrolysis of the crude reaction mixture with 6.0 M aq HCl at
rt for 80 h16 gave (2S,3R)-2-hydroxy-3-amino-8,8-dichlorooctanoic
OH
16, 79%, >99:1 dr
Scheme 4. Reagents and conditions: (i) Pd(OH)2/C (25% w/w), H2 (1 atm), MeOH, rt,
18 h; (ii) 6.0 M aq HCl, rt, 3 h then Dowex.
the requisite (E)-
of the resultant anti-
via sequential Swern oxidation/diastereoselective reduction to give
a
,b-unsaturated ester followed by epimerisation
a
-hydroxy-b-amino esters at the C(2)-position
the corresponding syn-
a
-hydroxy-b-amino esters as the key steps.
Ph
Ph
Ph
N
acid [(2S,3R)-dichloro-ahoa] 18 in 52% yield as
diastereoisomer (Scheme 6).
a single
Ph
N
(i)
Cl
CO2tBu
Cl
CO2tBu
OAc
OH
3. Conclusion
33, >99:1 dr
43, 93%, >99:1 dr
(ii)
In conclusion, the asymmetric syntheses of the N-terminal
a-
hydroxy-b-amino acid components of microginins 612, 646 and
680 were achieved via diastereoselective aminohydroxylation of
NHR1
NH2
(iv)
CO2tBu
CO2H
Cl
Cl
[R1 = Ac,
OH
20, 91%, >99:1 dr
R2 = H]
Ph
OR2
44, R1 = H, R2 = Ac
45, R1 = Ac, R2 = H,
(i)
Ph
N
CO2tBu
(iii)
R1
R1
CO2tBu
79% (from 43), >99:1 dr
R2
R2
OH
23, R1 = R2 = H, >99:1 dr [(E):(Z)]
25, R1 = Cl, R2 = H, >99:1 dr [(E):(Z)]
29, R1 = R2 = Cl, >99:1 dr [(E):(Z)]
Ph
Ph
32, R1 = R2 = H, 84%, >99:1 dr
33, R1 = Cl, R2 = H, 80%, >99:1 dr
34, R1 = R2 = Cl, 60%, >99:1 dr
Ph
N
Ph
N
(i)
Cl
CO2tBu
Cl
CO2tBu
OAc
(ii)
OH
39, >99:1 dr
46, 89%, >99:1 dr
Ph
Ph
(ii)
Ph
N
Ph
N
R1
CO2tBu
R1
CO2tBu
(iii)
NH2
NH2
(iv)
R2
O
Cl
CO2tBu
Cl
CO2H
85:15 [38:32]
93:7 [39:33]
95:5 [40:34]
R2
OH
35, R1 = R2 = H, >99:1 dr
36, R1 = Cl, R2 = H, >99:1 dr
37, R1 = R2 = Cl, >99:1 dr
38 R1 = R2 = H
,
, 57%, >99:1 dr
OH
17, 89% (from 46), >99:1 dr
39, R1 = Cl, R2 = H, 61%, >99:1 dr
40, R1 = R2 = Cl, 60%, >99:1 dr
OAc
47
Scheme 3. Reagents and conditions: (i) (R)-8, THF, ꢀ78 °C, 2 h then (ꢀ)-CSO 9,
ꢀ78 °C to rt, 18 h; (ii) (COCl)2, DMSO, CH2Cl2, ꢀ78 °C, 30 min then Et3N, ꢀ78 °C, 30
min; (iii) NaBH4, MeOH, ꢀ20 °C, 2 h.
Scheme 5. Reagents and conditions: (i) Ac2O, DMAP, pyridine, rt, 18 h; (ii) NaBrO3,
Na2S2O4, EtOAc/H2O (1:2), rt, 4 h; (iii) purification via column chromatography; (iv)
6.0 M aq HCl, 100 °C, 3 h, then Dowex.
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4
S. G. Davies et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Ph
ether/EtOAc, 98:2) gave 23 as a colourless oil (9.03 g, 87%, >99:1 dr
[(E):(Z)]);18 dH (400 MHz, CDCl3) 0.84–0.93 (3H, m, C(8)H3), 1.22–
1.38 (6H, m, C(5)H2, C(6)H2, C(7)H2), 1.49 (9H, s, CMe3), 2.10–
2.18 (2H, m, C(4)H2), 5.73 (1H, dt, J 15.6, 1.6, C(2)H), 6.86 (1H, dt,
J 15.6, 7.0, C(3)H).
Ph
N
NH2
Cl
CO2tBu
(ii)
Cl
CO2tBu
[R = Ac]
Cl
OR
Cl
OAc
34, R = H, >99:1 dr
48,R = Ac, 98%, >99:1 dr
49
(i)
4.1.2. tert-Butyl (E)-8-chlorooct-2-enoate 25
(iii) or (iv)
NH2
IBX (30.7 g, 110 mmol) was added to a stirred solution of 24
(4.88 mL, 36.6 mmol) in EtOAc (210 mL) at rt. The resultant mix-
ture was then stirred at 70 °C for 24 h, then allowed to cool to rt
and filtered (eluent EtOAc, 100 mL).
NH2
Cl
CO2H
Cl
CO2H
Cl
OH
OH
30 (13.8 g, 36.6 mmol) was added to a stirred solution of the
resultant crude mixture in EtOAc (330 mL) at rt and the resultant
mixture was stirred at rt for 18 h, then concentrated in vacuo.
Purification via flash column chromatography (eluent 30–40 °C
petroleum ether/EtOAc, 98:2) gave 25 as a colourless oil (7.05 g,
83%, >99:1 dr [(E):(Z)]); mmax 1711 (C@O); dH (400 MHz, CDCl3)
1.48 (9H, s, CMe3), 1.44–1.52 (4H, m, C(5)H2, C(6)H2), 1.72–1.84
(2H, m, C(7)H2), 2.10–2.20 (2H, m, C(4)H2), 3.53 (2H, t, J 6.7,
C(8)H2), 5.74 (1H, dt, J 15.6, 1.6, C(2)H), 6.84 (1H, dt, J 15.6, 6.9,
C(3)H); dC (100 MHz, CDCl3) 26.4, 27.4 (C(5), C(6)), 28.1 (CMe3),
31.8 (C(4)), 32.4 (C(7)), 44.9 (C(8)), 80.1 (CMe3), 123.3 (C(2)),
147.5 (C(3)), 166.0 (C(1)); m/z (ESI+) 257 ([M(37Cl)+Na]+, 32%), 255
21, (iv). 47% (from 48), >99:1 dr
(Z)-50/(E)-51, ~2:1 dr [(Z):(E)]
Ph
NH2
Ph
N
(ii), (iv)
Cl
CO2H
Cl
CO2tBu
[R = Ac]
Cl
OH
18, 52%, >99:1 dr
Cl
OR
40, R = H, >99:1 dr
(i)
52, R = Ac, 92%, >99:1 dr
Scheme 6. Reagents and conditions: (i) Ac2O, DMAP, pyridine, rt, 18 h; (ii) NaBrO3,
Na2S2O4, EtOAc/H2O (1:2), rt, 4 h; (iii) 6.0 M aq HCl, 100 °C, 3 h; (iv) 6.0 M aq HCl, rt,
18 h then Dowex.
([M(35Cl)+Na]+, 100%); HRMS (ESI+) C12H2137ClNaO2 ([M(37Cl)+Na]+)
+
requires 257.1093; found 257.1093; C12H2135ClNaO2 ([M(35Cl)+Na]+)
+
requires 255.1122; found 255.1122.
Suitable N-debenzylation (either catalytic hydrogenolysis or
NaBrO3-mediated oxidative N-debenzylation) of these syn- and
4.1.3. tert-Butyl (E)-8-oxooct-2-enoate 28
A solution of cyclohexene 26 (10.0 g, 122 mmol) in CH2Cl2 (240
mL) was cooled to ꢀ78 °C and degassed with N2 and O2 before O3
was bubbled through the solution until a persistent blue colour
appeared. O2 was then bubbled through the solution until it
became colourless. PPh3 (32.0 g, 122 mmol) was then added and
the reaction mixture was allowed to warm to rt and stirred at rt
4 h. Ylid 30 (13.7 g, 36.5 mmol) was added and the reaction mix-
ture was stirred at rt for 18 h, then concentrated in vacuo. The
resultant mixture was triturated with Et2O (3 ꢂ 200 mL) and the
combined organic extracts were dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30–40 °C
petroleum ether/EtOAc, 98:2 increased to 95:5) gave 28 as a
colourless oil (5.09 g, 66%, >99:1 dr [(E):(Z)]); mmax 1653, 1709
(C@O); dH (400 MHz, CDCl3) 1.41 (9H, s, CMe3), 1.40–1.49 (2H, m,
C(5)H2), 1.58 (2H, app dt, J 9.2, 7.2, C(6)H2), 2.13 (2H, td, J 6.9,
1.6, C(4)H2), 2.38 (2H, td, J 7.2, 1.7, C(7)H2), 5.68 (1H, dt, J 15.6,
1.6, C(2)H), 6.76 (1H, dt, J 15.6, 6.9, C(3)H), 9.70 (1H, t, J 1.7, C(8)H);
dC (100 MHz, CDCl3) 21.4 (C(6)), 27.4 (CMe3), 28.0 (C(5)), 31.5
(C(4)), 43.4 (C(7)), 80.0 (CMe3), 123.3 (C(2)), 146.8 (C(3)), 165.8
anti-
ysis gave the N-terminal syn-
of microginins 612, 646 and 680, and the corresponding C(2)-epi-
meric anti- -hydroxy-b-amino acids.
a
-hydroxy-b-amino esters, followed by acid mediated hydrol-
a-hydroxy-b-amino acid components
a
4. Experimental
4.1. General experimental
All reactions involving organometallic or other moisture-sensi-
tive reagents were carried out under a nitrogen atmosphere using
standard vacuum line techniques and glassware that was flame
dried and cooled under nitrogen before use. Solvents were dried
according to the procedure outlined by Grubbs and co-workers.17
BuLi was purchased as a solution in hexanes and titrated against
diphenylacetic acid before use. All other reagents were used as
supplied without prior purification. Organic layers were dried over
MgSO4. Thin layer chromatography was performed on aluminium
plates coated with 60 F254 silica. Plates were visualised using UV
light (254 nm), 1% aq KMnO4 or Dragendorff’s reagent. Flash col-
umn chromatography was performed on Kieselgel 60 silica. Melt-
ing points are uncorrected. Specific rotations are reported in
10ꢀ1 deg cm2 gꢀ1 and concentrations in g/100 mL. IR spectra were
recorded using an ATR module. Selected characteristic peaks are
reported in cmꢀ1. NMR spectra were recorded in the deuterated
solvent stated. Spectra were recorded at rt unless otherwise stated.
The field was locked by external referencing to the relevant deu-
teron resonance. 1H–1H COSY, 1H–13C HMQC, and 1H–13C HMBC
analyses were used to establish atom connectivity. Accurate mass
measurements were run on a TOF spectrometer internally cali-
brated with polyalanine.
(C(1)), 202.0 (C(8)); m/z (ESI+) 235 ([M+Na]+, 100%); HRMS (ESI+)
+
C
12H20NaO3 ([M+Na]+) requires 235.1305; found 235.1306.
4.1.4. tert-Butyl (E)-8,8-dichlorooct-2-enoate 29
A solution of 28 (500 mg, 3.53 mmol, >99:1 dr) in CH2Cl2 (3 mL)
was added to a stirred solution of ClPPh2 (0.66 mL, 3.54 mmol) and
NCS (470 mg, 3.53 mmol) in CH2Cl2 (9 mL) at rt and the resultant
mixture was stirred at rt for 4 h, then concentrated in vacuo. Purifi-
cation via flash column chromatography (eluent 30–40 °C petro-
leum ether/EtOAc, 98:2) gave 29 as a colourless oil (630 mg, 48%,
>99:1 dr); mmax 1791 (C@O); dH (400 MHz, CDCl3) 1.48 (9H, s,
CMe3), 1.49–1.65 (4H, m, C(5)H2, C(6)H2), 2.15–2.31 (4H, m,
C(4)H2, C(7)H2), 5.68–5.80 (2H, m, C(2)H, C(8)H), 6.83 (1H, dt, J 15.5,
6.9, C(3)H); dC (100 MHz, CDCl3) 25.3 (C(6)), 26.7 (C(5)), 28.0
(CMe3), 31.5 (C(4)), 43.1 (C(7)), 73.1 (C(8)), 80.2 (CMe3), 123.4 (C(2)),
146.8 (C(3)), 165.8 (C(1)); m/z (ESI+) 293 ([M(37Cl2)+Na]+, 10%),
291 ([M(35Cl,37Cl)+Na]+, 64%), 289 ([M(35Cl2)+Na]+, 100%); HRMS
4.1.1. tert-Butyl (E)-oct-2-enoate 23
6-Hexanal (6.42 mL, 52.2 mmol) was added to a stirred solution
of 30 (19.8 g, 52.2 mmol) in CH2Cl2 (470 mL). The resultant mix-
ture was stirred at rt for 48 h, then concentrated in vacuo. Purifica-
tion via flash column chromatography (eluent 30–40 °C petroleum
(ESI+) C12H2037Cl2NaO2 ([M(37Cl2)+Na]+) requires 293.0674;
+
found 293.0679; C12H2035Cl37ClNaO2+ ([M(35Cl,37Cl)+Na]+) requires
Please cite this article in press as: Davies, S. G.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.09.022

S. G. Davies et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
291.0703; found 291.0709; C12H2035Cl2NaO2 ([M(35Cl2)+Na]+)
requires 289.0733; found 289.0744.
C
C
27H3937ClNO3 ([M(37Cl)+H]+) requires 462.2583; found 462.2601;
27H3935ClNO3+ ([M(35Cl)+H]+) requires 460.2613; found 460.2625.
+
+
4.1.5. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-
a
-(methyl-
4.1.7. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-a-(methyl-
benzyl)amino]octanoate 32
benzyl)amino]-8,8-dichlorooctanoate 34
BuLi (2.5 M in hexanes, 28.3 mL, 70.7 mmol) was added drop-
wise to a stirred solution of (R)-N-benzyl-N-( -methylbenzyl)-
BuLi (2.5 M in hexanes, 5.98 mL, 5.90 mmol) was added drop-
wise to a stirred solution of (R)-N-benzyl-N-( -methylbenzyl)-
a
a
amine (15.4 g, 73.0 mmol, >99:1 er) in THF (203 mL) at ꢀ78 °C.
The reaction mixture was stirred at ꢀ78 °C for 30 min, then a solu-
tion of 23 (9.04 g, 45.6 mmol, >99:1 dr [(E):(Z)]) in THF (101 mL)
was added dropwise at ꢀ78 °C and the resultant mixture was stir-
red at ꢀ78 °C for 2 h. (ꢀ)-CSO 9 (16.2 g, 70.7 mmol) was added and
the resultant mixture was allowed to warm to rt and stirred at rt
for 18 h. The reaction mixture was then concentrated in vacuo
and partitioned between CH2Cl2 (100 mL) and 10% aq citric acid
(100 mL). The aqueous layer was extracted with CH2Cl2 (3 ꢂ 100
mL), and the combined organic extracts were washed with satd
aq NaHCO3 (200 mL), then dried and concentrated in vacuo. The
residue was triturated with Et2O (200 mL), then filtered and con-
centrated in vacuo. Purification via flash column chromatography
(eluent 30–40 °C petroleum ether/EtOAc, 98:2) gave 32 as a colour-
amine (3.22 g, 15.3 mmol, >99:1 er) in THF (93 mL) at ꢀ78 °C. The
reaction mixture was stirred at ꢀ78 °C for 30 min, then a solution
of 29 (1.24 g, 5.86 mmol, >99:1 dr [(E):(Z)]) in THF (13 mL) was
added dropwise at ꢀ78 °C and the resultant mixture was stirred
at ꢀ78 °C for 2 h. (ꢀ)-CSO 9 (3.49 g, 15.3 mmol) was added and
the resultant mixture was allowed to warm to rt and stirred at rt
for 18 h. The reaction mixture was then concentrated in vacuo
and partitioned between CH2Cl2 (40 mL) and 10% aq citric acid
(40 mL). The aqueous layer was extracted with CH2Cl2 (3 ꢂ 50
mL), and the combined organic extracts were washed with satd
aq NaHCO3 (50 mL), then dried and concentrated in vacuo. The resi-
due was triturated with Et2O (50 mL), then filtered and concen-
trated in vacuo. Purification via flash column chromatography
(eluent 30–40 °C petroleum ether/EtOAc, 98:2) gave 34 as colour-
less oil (16.3 g, 84%, >99:1 dr); ½a D25
ꢃ
ꢀ27.0 (c 1.0 in CHCl3); mmax
less oil (1.73 g, 60%, >99:1 dr); ½a D25
ꢀ19.0 (c 1.0 in CHCl3); mmax
ꢃ
3501 (br, OAH), 1719 (C@O); dH (400 MHz, CDCl3) 0.80 (3H, t,
3501 (br, OAH), 1719 (C@O); dH (400 MHz, CDCl3) 1.21 (3H, d,
J 7.3, C(8)H3), 1.08 (3H, d, J 6.9, C(a)Me), 1.17–1.50 (6H, m, C(5)H2,
J 7.1, C(a)Me), 1.23–1.34 (4H, m, C(5)H2, C(6)H2), 1.36 (9H, s,
C(6)H2, C(7)H2), 1.34 (9H, s, CMe3), 1.60–1.75 (2H, m, C(4)H2),
2.84 (1H, d, J 6.1, OH), 3.12 (1H, ddd, J 8.6, 4.8, 1.8, C(3)H), 3.60
CMe3), 1.40–1.63 (2H, m, C(4)H2), 2.02–2.11 (2H, m, C(7)H2), 2.84
(1H, d, J 5.7, OH), 3.12 (1H, ddd, J 9.3, 4.2, 1.6, C(3)H), 3.60 (1H, d,
(1H, d, J 15.4, NCHAHBPh), 3.81–3.92 (2H, m, C(2)H, C(
(1H, d, J 15.4, NCHAHBPh), 7.10–7.40 (10H, m, Ph); dC (100 MHz,
CDCl3) 14.6 (C(8)), 19.9 (C( )Me), 23.1, 26.8, 27.8 (C(5), C(6),
C(7)), 28.5 (CMe3), 32.4 (C(4)), 51.5 (NCH2Ph), 59.0 (C(3)), 59.2
a
)H), 4.18
J 15.6, NCHAHBPh), 3.79–3.93 (2H, m, C(2)H, C(
J 15.6, NCHAHBPh), 5.60 (1H, t, J 6.0, C(8)H), 7.12–7.39 (10H, m, Ph);
dC (100 MHz, CDCl3) 20.3 (C( )Me), 25.2, 26.2 (C(5), C(6)), 27.3
(C(4)), 28.2 (CMe3), 43.6 (C(7)), 51.0 (NCH2Ph), 58.8 (C(3)), 59.2
(C( )), 71.0 (C(2)), 73.7 (C(8)), 82.8 (CMe3), 126.5, 127.2, 128.0,
a)H), 4.22 (1H, d,
a
a
(C(
a
)), 71.6 (C(2)), 82.8 (CMe3), 126.2, 126.8, 127.4, 128.5, 128.6,
a
128.7 (o,m,p-Ph), 144.0, 143.2 (i-Ph), 174.9 (C(1)); m/z (ESI+) 426
128.2, 128.3, 128.4 (o,m,p-Ph), 143.8, 142.9 (i-Ph), 174.5 (C(1));
([M+H]+, 100%); HRMS (ESI+) C27H40NO3 ([M+H]+) requires
m/z (ESI+) 498 ([M(37Cl2)+H]+, 10%), 496 ([M(35Cl,37Cl)+H]+, 64%), 494
+
([M(35Cl2)+H]+, 100%); HRMS (ESI+) C27H3837Cl2NO3 ([M(37Cl2)
+
426.3003; found 426.2996.
+H]+) requires 498.2164; found 494.2188; C27H3835Cl37ClNO3
+
([M(35Cl,37Cl)+H]+) requires 496.2194; found 494.2206; C27H3835Cl2NO3
+
4.1.6. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-a-(methyl-
benzyl)amino]-8-chlorooctanoate 33
([M(35Cl2)+H]+) requires 494.2223; found 494.2231.
BuLi (2.5 M in hexanes, 12.9 mL, 32.4 mmol) was added drop-
wise to a stirred solution of (R)-N-benzyl-N-( -methylbenzyl)-
a
4.1.8. tert-Butyl (2S,3R,aR)-2-hydroxy-3-[N-benzyl-N-a-(methyl-
amine (7.05 g, 33.4 mmol, >99:1 er) in THF (93 mL) at ꢀ78 °C.
The reaction mixture was stirred at ꢀ78 °C for 30 min, then a solu-
tion of 25 (4.41 g, 20.9 mmol, >99:1 dr [(E):(Z)]) in THF (46 mL)
was added dropwise at ꢀ78 °C and the resultant mixture was stir-
red at ꢀ78 °C for 2 h. (ꢀ)-CSO 9 (7.42 g, 32.4 mmol) was added and
the resultant mixture was allowed to warm to rt and stirred at rt
for 18 h. The reaction mixture was then concentrated in vacuo
and partitioned between CH2Cl2 (100 mL) and 10% aq citric acid
(100 mL). The aqueous layer was extracted with CH2Cl2 (3 ꢂ 50
mL), and the combined organic extracts were washed with satd
aq NaHCO3 (200 mL), then dried and concentrated in vacuo. The
residue was triturated with Et2O (200 mL), then filtered and con-
centrated in vacuo. Purification via flash column chromatography
(eluent 30–40 °C petroleum ether/EtOAc, 98:2) gave 33 as colour-
benzyl)amino]octanoate 38
Step 1: DMSO (1.50 mL, 18.8 mmol) was added to a stirred solu-
tion of (COCl)2 (0.80 mL, 9.41 mmol) in CH2Cl2 (16 mL) and the
resultant mixture was stirred at ꢀ78 °C for 20 min. A solution of
32 (2.00 g, 4.70 mmol, >99:1 dr) in CH2Cl2 (8.0 mL) was then added
dropwise at ꢀ78 °C and the resultant mixture was stirred at ꢀ78 °C
for 30 min. Et3N (3.95 mL, 28.2 mmol) was then added and the
resultant mixture was stirred at ꢀ78 °C for 30 min then allowed
to warm rt. H2O (15 mL) was added and the aqueous layer was
extracted with CH2Cl2 (3 ꢂ 15 mL). The combined organic extracts
were then dried and concentrated in vacuo.
Step 2: NaBH4 (178 mg, 4.70 mmol) was added to a stirred solu-
tion of the residue of 35 in MeOH (23.5 mL) at ꢀ20 °C and the
resultant mixture was stirred at ꢀ20 °C for 2 h, then allowed to
warm to rt. The reaction mixture was then concentrated in vacuo
and partitioned between CH2Cl2 (20 mL) and H2O (20 mL). The
aqueous layer was extracted with CH2Cl2 (3 ꢂ 20 mL), and the
combined organic extracts were dried and concentrated in vacuo
to give an 85:15 mixture of 38 and 32, respectively. Purification
via flash column chromatography (eluent 30–40 °C petroleum
ether/Et2O, 95:5) gave 38 as a colourless oil (1.14 g, 57%, >99:1
less oil (7.68 g, 80%, >99:1 dr); ½a D25
ꢀ23.7 (c 1.0 in CHCl3); mmax
ꢃ
3084 (br, OAH), 1717 (C@O); dH (400 MHz, CDCl3) 0.99–1.61
(6H, m, C(4)H2, C(5)H2, C(6)H2), 1.21 (3H, d, J 7.0, C(a)Me), 1.36
(9H, s, CMe3), 1.62–1.71 (2H, m, C(7)H2), 2.83 (1H, d, J 5.9, OH),
3.12 (1H, ddd, J 8.9, 4.5, 1.7, C(3)H), 3.43 (2H, t, J 6.7, C(8)H2),
3.60 (1H, d, J 15.6, NCHAHBPh), 3.86–3.90 (2H, m, C(2)H, C(
4.20 (1H, d, J 15.6, NCHAHBPh), 7.18–7.43 (10H, m, Ph); dC (100
MHz, CDCl3) 19.7 (C( )Me), 27.8 (CMe3), 25.7, 26.8, 27.0 (C(4),
C(5), C(6)), 32.4 (C(7)), 44.9 (C(8)), 50.8 (NCH2Ph), 58.5, 58.7 (C( ),
a)H),
a
dr); ½a 2D5
ꢀ24.4 (c 1.0 in CHCl3); mmax 3658 (br, OAH), 1720
ꢃ
a
(C@O); dH (400 MHz, CDCl3) 0.85 (3H, t, J 7.0, C(8)H3), 1.31 (3H,
C(3)), 70.8 (C(2)), 82.3 (CMe3), 126.2, 126.8, 127.8, 127.9, 127.9,
128.0 (o,m,p-Ph), 142.4, 143.5 (i-Ph), 174.2 (C(1)); m/z (ESI+) 462
([M(37Cl)+H]+, 32%); 460 ([M(35Cl)+H]+, 100%); HRMS (ESI+)
d, J 7.0, C(a)Me), 1.36 (9H, s, CMe3), 1.11–1.58 (8H, m, C(4)H2,
C(5)H2, C(6)H2, C(7)H2), 2.99 (1H, app q, J 6.3, C(3)H), 3.41 (1H, br
s, OH), 3.70–3.80 (2H, m, C(2)H, NCHAHBPh), 3.84 (1H, d, J 14.5,
Please cite this article in press as: Davies, S. G.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.09.022

6
S. G. Davies et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
NCHAHBPh), 4.03 (1H, q, J 7.0, C(
(100 MHz, CDCl3) 14.6 (C(8)), 18.0 (C(
a
)H), 7.14–7.35 (10H, m, Ph); dC
)Me), 23.0, 27.9, 29.2, 32.7
(C(4), C(5), C(6), C(7)), 28.5 (CMe3), 50.8 (NCH2Ph), 61.2 (C( )),
ꢀ15.0 (c 1.0 in CHCl3); mmax 3503 (br, OAH), 1722 (C@O); dH
(400 MHz, CDCl3) 1.29 (3H, d, J 7.0, C( )Me), 1.35 (9H, s, CMe3),
1.14–1.61 (6H, m, C(4)H2, C(5)H2, C(6)H2), 1.99–2.10 (2H, m, C(7)H2),
a
a
a
61.3 (C(3)), 73.9 (C(2)), 82.2 (CMe3), 127.2, 127.6, 128.3, 128.7,
2.96–2.99 (1H, m, C(3)H), 3.20 (1H, br s, OH), 3.70–3.79 (2H, m,
128.8, 129.0 (o,m,p-Ph), 143.8, 142.7 (i-Ph), 174.6 (C(1));
NCH2Ph), 3.82 (1H, d, J 14.7, C(2)H), 3.98–4.05 (1H, m, C(
5.62 (1H, t, J 6.0, C(8)H), 7.12–7.25 (10H, m, Ph); dC (100 MHz,
CDCl3) 18.3 (C( )Me), 26.2, 26.5, 28.4 (C(4), C(5), C(6)), 28.1
(CMe3), 43.3 (C(7)), 50.2 (NCH2Ph), 60.7 (C( )), 61.2 (C(3)), 73.4
a)H),
m/z (ESI+) 426 ([M+H]+, 100%); HRMS (ESI+) C27H40NO3 ([M+H]+)
+
requires 426.3003; found 426.2996.
a
a
4.1.9. tert-Butyl (2S,3R,
benzyl)amino]-8-chlorooctanoate 39
a
R)-2-hydroxy-3-[N-benzyl-N-
a
-(methyl-
(C(2)), 73.5 (C(8)), 82.0 (CMe3), 126.8, 127.3 (p-Ph), 127.9, 128.3,
128.4, 128.5 (o,m,p-Ph), 141.5, 143.2 (i-Ph), 173.18 (C(1));
m/z (ESI+) 498 ([M(37Cl2)+H]+, 10%), 496 ([M(35Cl,37Cl)+H]+, 64%),
494 ([M(35Cl2)+H]+, 100%); HRMS (ESI+) C27H3837Cl2NO3+ ([M(37Cl2)
Step 1: DMSO (1.73 mL, 24.2 mmol) was added to a stirred solu-
tion of (COCl)2 (1.02 mL, 12.1 mmol) in CH2Cl2 (10 mL) and the
resultant mixture was stirred at ꢀ78 °C for 20 min. A solution of
33 (2.78 g, 6.05 mmol, >99:1 dr) in CH2Cl2 (22 mL) was then added
dropwise at ꢀ78 °C and the resultant mixture was stirred at ꢀ78 °C
for 30 min. Et3N (5.09 mL, 36.3 mmol) was then added and the
resultant mixture was stirred at ꢀ78 °C for 30 min then allowed
to warm rt H2O (30 mL) was added and the aqueous layer was
extracted with CH2Cl2 (3 ꢂ 30 mL). The combined organic extracts
were then dried and concentrated in vacuo.Step 2: NaBH4 (229 mg,
6.05 mmol) was added to a stirred solution of the residue of 36 in
MeOH (24 mL) at ꢀ20 °C and the resultant mixture was stirred at
ꢀ20 °C for 2 h, then allowed to warm to rt. The reaction mixture
was then concentrated in vacuo and partitioned between CH2Cl2
(20 mL) and H2O (20 mL). The aqueous layer was extracted with
CH2Cl2 (3 ꢂ 20 mL), and the combined organic extracts were dried
and concentrated in vacuo to give an 93:7 mixture of 39 and 33,
respectively. Purification via flash column chromatography (eluent
30–40 °C petroleum ether/Et2O, 95:5) gave 39 as a colourless oil
+
+H]+) requires 498.2164; found 494.2188; C27H3835Cl37ClNO3
([M(35Cl,37Cl)+H]+) requires 496.2194; found 494.2206;
C
27H3835Cl2NO3+ ([M(35Cl2)+H]+) requires 494.2223; found 494.2230.
4.1.11. tert-Butyl (R,R)-2-hydroxy-3-aminooctanoate 41
Pd(OH)2/C (13 mg, 25% w/w) was added to a degassed solution
of 32 (54 mg, 0.13 mmol, >99:1 dr) in MeOH (1.3 mL). The resul-
tant mixture was stirred under H2 (1 atm) at rt for 18 h. The reac-
tion mixture was then filtered through CeliteÒ (eluent MeOH) and
concentrated in vacuo to give 41 as a yellow oil (28 mg, 96%, >99:1
dr); ½a 2D5
ꢃ
+8.3 (c 1.0 in CHCl3); mmax 3672 (br, NAH, OAH), 1728
(C@O); dH (400 MHz, CDCl3) 0.88 (3H, t, J 6.9, C(8)H3), 1.22–1.48
(6H, m, C(5)H2, C(6)H2, C(7)H2), 1.49 (9H, s, CMe3), 1.51–1.55 (2H,
m, C(4)H2), 2.97–3.00 (1H, m, C(3)H), 4.01–4.06 (1H, m, C(2)H);
dC (100 MHz, CDCl3) 14.5 (C(8)), 28.5 (CMe3), 23.0, 26.6, 32.3
(C(5), C(6), C(7)), 34.8 (C(4)), 54.9 (C(3)), 75.3 (C(2)), 83.0 (CMe3),
173.2 (C(1)); m/z (ESI+) 232 ([M+H]+, 100%); HRMS (ESI+)
(1.70 g, 61%, >99:1 dr); ½a D25
ꢃ
ꢀ20.8 (c 1.0 in CHCl3); mmax 3062
C
12H26NO3 ([M+H]+) requires 232.1907; found 232.1906.
+
(br, OAH), 1721 (C@O); dH (400 MHz, CDCl3) 1.31 (3H, d, J 7.0,
C(
a
)Me), 1.39 (9H, s, CMe3), 1.17–1.55 (6H, m, C(4)H2, C(5)H2,
4.1.12. (R,R)-2-Hydroxy-3-aminooctanoic acid [(R,R)-ahoa] 19
A solution of 41 (261 mg, 1.13 mmol, >99:1 dr) in 6.0 M aq HCl
(10 mL) was stirred at rt for 3 h, then concentrated in vacuo. Purifi-
cation via ion-exchange chromatography (Dowex 50WX8-100, elu-
ent 1.0 M aq NH4OH) gave 19 as a white solid (119 mg, 60%, >99:1
C(6)H2), 1.60–1.72 (2H, m, C(7)H2), 2.98 (1H, ddd, J 7.8, 6.1, 4.6,
C(3)H), 3.28 (1H, d, J 3.3, OH), 3.45 (2H, t, J 6.7, C(8)H2), 3.71–3.77
(2H, m, C(2)H, NCHAHBPh), 3.82 (1H, d, J 14.6, NCHAHBPh), 4.02
(1H, q, J 7.0, C(
18.0 (CMe3), 28.0 (C(
(C(7)), 45.0 (C(8)), 50.2 (NCH2Ph), 60.3 (C(
a
)H), 7.12–7.30 (10H, m, Ph); dC (100 MHz, CDCl3)
)Me), 26.9, 27.2, 28.5 (C(4), C(5), C(6)), 32.4
)), 61.0 (C(3)), 73.5
a
dr);6 mp 243–244 °C; ½a 2D5
ꢃ
+3.6 (c 1.0 in MeOH); mmax 3672 (br,
a
NAH, OAH), 2997 (CAH), 1583 (C@O); dH (400 MHz, D2O) 0.83
(3H, t, J 7.0, C(8)H3), 1.24–1.45 (6H, m, C(5)H2, C(6)H2, C(7)H2),
1.42–1.68 (2H, m, C(4)H), 3.54–3.56 (1H, m, C(3)H), 4.21 (1H, d,
J 3.6, C(2)H); dC (100 MHz, CDCl3) 13.1 (C(8)), 21.6, 24.4, 26.9
(C(5), C(6), C(7)), 32.0 (C(4)), 54.0 (C(3)), 71.6 (C(2)), 176.7 (C(1));
(C(2)), 81.9 (CMe3), 127.2, 126.8, 128.29, 127.9, 128.5, 128.3 (o,m,
p-Ph), 143.3, 141.4 (i-Ph), 173.2 (C(1)); m/z (ESI+) 462 ([M(37Cl)+H+,
32%), 460 ([M(35Cl)+H]+, 100%); HRMS (ESI+) C27H3937ClNO3
+
([M(37Cl)+H]+) requires 462.2583; found 462.2592; C27H3935ClNO3
+
([M(35Cl)+H]+) requires 460.2613; found 460.2605.
m/z (ESI+) 176 ([M+H]+, 100%); HRMS (ESI+) C8H18NO3 ([M+H]+)
+
requires 176.12812; found 176.12824.
4.1.10. tert-Butyl (2S,3R,aR)-2-hydroxy-3-[N-benzyl-N-a-(methyl-
benzyl)amino]-8,8-dichlorooctanoate 40
4.1.13. tert-Butyl (2S,3R)-2-hydroxy-3-aminooctanoate 42
Pd(OH)2/C (116 mg, 25% w/w) was added to a degassed solution
of 38 (465 mg, 1.09 mmol, >99:1 dr) in MeOH (11 mL). The resul-
tant mixture was stirred under H2 (1 atm) at rt for 18 h. The reac-
tion mixture was then filtered through CeliteÒ (eluent MeOH) and
concentrated in vacuo to give 42 as a yellow oil (229 mg, 91%,
Step 1: DMSO (1.50 mL, 18.8 mmol) was added to a stirred solu-
tion of (COCl)2 (0.80 mL, 9.41 mmol) in CH2Cl2 (0.3 mL) and the
resultant mixture was stirred at ꢀ78 °C for 20 min. A solution of
34 (100 mg, 0.238 mmol, >99:1 dr) in CH2Cl2 (0.9 mL) was then
added dropwise at ꢀ78 °C and the resultant mixture was stirred
at ꢀ78 °C for 30 min. Et3N (0.19 mL, 1.39 mmol) was then added
and the resultant mixture was stirred at ꢀ78 °C for 30 min then
allowed to warm rt. H2O (5 mL) was added and the aqueous layer
was extracted with CH2Cl2 (3 ꢂ 5 mL). The combined organic
extracts were then dried and concentrated in vacuo.
>99:1 dr); ½a 2D5
ꢀ11.0 (c 1.0 in CHCl3); mmax 3673 (br, OAH,
ꢃ
NAH), 1734 (C@O); dH (400 MHz, CDCl3) 0.90 (3H, t, J 6.9,
C(8)H3), 1.18–1.42 (6H, m, C(5)H2, C(6)H2, C(7)H2), 1.43 (9H, s, CMe3),
1.45–1.54 (2H, m, C(4)H2), 2.99–3.04 (1H, m, C(3)H), 3.95–4.01
(1H, m, C(2)H); dC (100 MHz, CDCl3) 14.2 (C(8)), 22.8, 26.3,
32.0 (C(5), C(6), C(7)), 34.7 (C(4)), 28.2 (CMe3), 54.0 (C(3)), 73.8 (C(2)),
82.6 (CMe3), 173.9 (C(1)); m/z (ESI+) 232 ([M+H]+, 100%); HRMS
Step 2: NaBH4 (9 mg, 0.238 mmol) was added to a stirred solu-
tion of the residue of 36 in MeOH (23.5 mL) at ꢀ20 °C and the
resultant mixture was stirred at ꢀ20 °C for 2 h, then allowed to
warm to rt. The reaction mixture was then concentrated in vacuo
and partitioned between CH2Cl2 (5 mL) and H2O (5 mL). The aque-
ous layer was extracted with CH2Cl2 (3 ꢂ 5 mL), and the combined
organic extracts were dried and concentrated in vacuo to give an
95:5 mixture of 40 and 34, respectively. Purification via flash col-
umn chromatography (eluent 30–40 °C petroleum ether/EtOAc,
(ESI+) C12H26NO3 ([M+H]+) requires 232.1907; found 232.1907.
+
4.1.14. (2S,3R)-2-Hydroxy-3-aminooctanoic acid [(2S,3R)-ahoa]
16
A solution of 42 (150 mg, 0.649 mmol, >99:1 dr) in 6.0 M aq HCl
(5 mL) was stirred at rt for 3 then concentrated in vacuo. Purifica-
tion via ion-exchange chromatography (Dowex 50WX8-100, elu-
ent 1.0 M aq NH4OH) gave 16 as a white solid (90 mg, 79%, >99:1
98:2) gave 40 as a colourless oil (60 mg, 60%, >99:1 dr); ½a D25
ꢃ
Please cite this article in press as: Davies, S. G.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.09.022

S. G. Davies et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
dr);6 mp 242.5–243.5 °C; ½a 2D5
ꢃ
ꢀ6.0 (c 1.0 in H2O/MeOH (v/v, 1:1));
Purification via ion-exchange chromatography (Dowex 50WX8-
100, eluent 1.0 M aq NH4OH) gave 20 as a white solid (139 mg,
m
max 3672 (br, NAH, OAH), 2998 (CAH), 1591 (C@O); dH (400 MHz,
D2O) 0.75 (3H, t, J 7.1, C(8)H3), 1.71–1.41 (6H, m, C(5)H2, C(6)H2,
C(7)H2), 1.48–1.67 (2H, m, C(4)H2), 3.33–3.37 (1H, m, C(3)H),
3.97 (1H, d, J 3.9, C(2)H); dC (100 MHz, CDCl3) 13.1 (C(8)), 21.6,
24.3, 30.5 (C(5), C(6), C(7)), 29.0 (C(4)), 54.0 (C(3)), 70.9 (C(2)),
177.7 (C(1)); m/z (ESI+) 176 ([M+H]+, 100%); HRMS (ESI+)
91%, >99:1 dr); mp 185.5–186.5 °C; ½a D25
ꢃ
+20.4 (c 1.0 in MeOH);
mmax 3420 (br, OAH, NAH), 1590 (C@O); dH (400 MHz, MeOH-d4)
1.37–1.53 (4H, m, C(5)H2, C(6)H2), 1.54–1.74 (2H, m, C(4)H2),
1.73–1.82 (2H, m, C(7)H2), 3.30–3.36 (1H, m, C(3)H), 3.56 (2H, t,
J 6.6, C(8)H), 3.99 (1H, d, J 3.0, C(2)H); dC (100 MHz, MeOH-d4)
25.8, 27.7 (C(5), C(6)), 30.8 (C(4)), 33.5 (C(7)), 45.5 (C(8)), 55.2
(C(3)), 71.6 (C(2)), 177.1 (C(1)); m/z (ESI+) 212 ([M(37Cl)+H+, 32%);
C8H18NO3 ([M+H]+) requires 176.12812; found 176.12816.
+
210 ([M(35Cl)+H]+, 100%); HRMS (ESI+) C8H1737ClNO3 ([M(37Cl)
+
4.1.15. tert-Butyl (R,R,R)-2-acetoxy-3-[N-benzyl-N-a-(methyl-
benzyl)amino]-8-chlorooctanoate 43
+H]+) requires 212.0862; found 212.0871; C8H1735ClNO3+ ([M(35Cl)
+H]+) requires 210.0891; found 210.0900.
Ac2O (1.15 mL, 12.3 mmol) and DMAP (14 mg, 0.123 mmol)
were added to a stirred solution of 33 (543 mg, 1.23 mmol, >99:1
dr) in pyridine (5.0 mL) at 0 °C. The resultant mixture was allowed
to warm to rt and stirred at rt for 18 h. The reaction mixture was
then diluted with H2O (6 mL) and EtOAc (6 mL), and the aqueous
layer was extracted with EtOAc (3 ꢂ 6 mL). The combined organic
extracts were washed with brine (20 mL), then dried and concen-
trated in vacuo. Purification via flash column chromatography gave
4.1.18. tert-Butyl (2S,3R,aR)-2-acetoxy-3-[N-benzyl-N-a-(methyl-
benzyl)amino]-8-chlorooctanoate 46
Ac2O (1.08 mL, 11.2 mmol) and DMAP (13 mg, 0.112 mmol)
were added to a stirred solution of 39 (523 mg, 1.14 mmol, >99:1
dr) in pyridine (4.8 mL) at 0 °C. The resultant mixture was allowed
to warm and stirred at rt for 18 h. The reaction mixture was then
diluted with H2O (5 mL) and EtOAc (5 mL), and the aqueous later
was extracted with EtOAc (2 ꢂ 5 mL). The combined organic
extracts were washed with brine (15 mL), then dried and concen-
trated in vacuo. Purification via flash column chromatography (elu-
ent 40–60 °C petroleum ether/Et2O, 90:10) gave 46 as a colourless
43 as a white solid (573 mg, 93%, >99:1 dr); mp 85.5–86.5 °C; ½a D25
ꢃ
+1.8 (c 1.0 in CHCl3); mmax 1742 (C@O); dH (400 MHz, CDCl3) 1.16
(3H, d, J 7.0, C(a)Me), 1.31 (9H, s, CMe3), 1.10–1.54 (6H, m, C(4)H2,
C(5)H2, C(6)H2), 1.56–1.72 (2H, m, C(7)H2), 1.99 (3H, s, COMe),
3.22 (1H, ddd, J 9.9, 3.8, 1.4, C(3)H), 3.40 (2H, t, J 6.8, C(8)H2),
3.49 (1H, d, J 15.6, NCHAHBPh), 3.86 (1H, q, J 7.0, C(
(1H, d, J 15.6, NCHAHBPh), 4.95 (1H, d, J 3.8, C(2)H), 7.13–7.38
(10H, m, Ph); dC (100 MHz, CDCl3) 21.1 (C( )Me), 21.6 (COMe),
26.2, 26.9, 28.0, 32.6 (C(4), C(5), C(6), C(7)), 28.1 (CMe3), 45.1
(C(8)), 50.6 (NCH2Ph), 57.7 (C(3)), 60.2 (C( )), 73.0 (C(2)), 82.3
a)H), 4.12
oil (509 mg, 89%, >99:1 dr); ½a D25
ꢃ
+1.1 (c 1.0 in CHCl3); mmax 1741
(C@O); dH (400 MHz, CDCl3) 1.10–1.40 (6H, m, C(4)H2, C(5)H2,
a
C(6)H2), 1.21 (3H, d, J 6.9, C(a)Me), 1.38 (9H, s, CMe3), 1.56–1.67
(2H, m, C(7)H2), 1.93 (3H, s, COMe), 3.21 (1H, td, J 6.8, 4.6, C(3)H),
3.40 (2H, t, J 6.7, C(8)H2), 3.83–3.90 (2H, m, NCH2Ph), 4.04 (1H,
a
(CMe3), 126.7, 127.2, 127.8, 128.0, 128.4, 128.5 (o,m,p-Ph), 142.9,
q, J 6.9, C(
dC (100 MHz, CDCl3) 20.0 (C(
32.5 (C(4), C(5), C(6), C(7)), 28.1 (CMe3), 45.1 (C(8)), 50.9 (NCH2Ph),
59.6 (C(3)), 60.1 (C( )), 75.9 (C(2)), 82.2 (CMe3), 126.5, 127.1, 127.8,
a
)H), 4.78 (1H, d, J 4.6, C(2)H), 7.10–7.36 (10H, m, Ph);
144.1 (i-Ph), 168.8, 170.4 (C(1), COMe); m/z (ESI+) 504 ([M(37Cl)+H]+,
a)Me), 20.8 (COMe), 26.5, 26.9, 28.6,
32%), 502 ([M(35Cl)+H]+, 100%); HRMS (ESI+) C29H4137ClNO4
+
([M(37Cl)+H]+) requires 504.2689; found 504.2715; C29H4135ClNO4
a
+
([M(35Cl)+H]+) requires 502.2719; found 502.2733.
128.1, 128.2, 128.4 (o,m,p-Ph), 142.5, 143.9 (i-Ph), 168.7, 170.5
(C(1), COMe); m/z (ESI+) 504 ([M(37Cl)+H]+, 32%), 502 ([M(35Cl)+H]+,
100%); HRMS (ESI+) C29H4137ClNO4 ([M(37Cl)+H]+) requires
+
4.1.16. tert-Butyl (R,R)-2-hydroxy-3-acetamido-8-chlorooctanoate
45
504.2689; found 504.2708; C29H4135ClNO4+ ([M(35Cl)+H]+) requires
502.2719; found 502.2748.
A solution of NaBrO3 (398 mg, 2.63 mmol) in H2O (9.0 mL) was
added to a stirred solution of 43 (440 mg, 0.878 mmol, >99;1 dr) in
EtOAc (12 mL) at rt and the resultant mixture was stirred at rt for
10 min. A solution of Na2S2O4 (382 mg, 2.19 mmol) in H2O (16 mL)
was added dropwise at rt over 5 min then the reaction mixture was
stirred at rt for 4 h. EtOAc (15 mL) was added and the resultant
mixture was washed with satd aq Na2S2O3 (15 mL). The aqueous
layer was extracted with EtOAc (2 ꢂ 15 mL) and the combined
organic extracts were washed with brine (35 mL), then dried and
concentrated in vacuo. Purification via flash column chromatogra-
phy (eluent 30–40 °C petroleum ether/EtOAc, 40:60) gave 45 as a
4.1.19. (2S,3R)-2-Hydroxy-3-amino-8-chlorooctanoic acid
[(2S,3R)-chloro-ahoa] 17
Step 1: A solution of NaBrO3 (1.09 g, 7.24 mmol) in H2O (25 mL)
was added to a stirred solution of 46 (1.21 g, 2.41 mmol, >99:1 dr)
in EtOAc (33 mL) at rt and the resultant mixture was stirred at rt
for 10 min. A solution of Na2S2O4 (1.05 g, 6.03 mmol) in H2O (44
mL) was added dropwise at rt over 5 min then the reaction mixture
was stirred at rt for 4 h. EtOAc (30 mL) was added and the resultant
mixture was washed with satd aq Na2S2O3 (50 mL). The aqueous
layer was extracted with EtOAc (2 ꢂ 50 mL) and the combined
organic extracts were washed with brine (100 mL), then dried
and concentrated in vacuo.
yellow oil (213 mg, 79%, >99:1 dr); ½a D25
ꢀ3.2 (c 1.0 in CHCl3); mmax
ꢃ
3294 (br, OAH, NAH), 1733 (C@O, ester), 1653 (C@O, amide); dH
(400 MHz, CDCl3) 1.51 (9H, s, CMe3), 1.16–1.58 (6H, m, C(4)H2, C
(5)H2, C(6)H2), 1.75 (2H, m, C(7)H2), 2.02 (3H, s, COMe), 3.08 (1H, d,
J 5.2, OH), 3.52 (2H, t, J 6.0, C(8)H2), 4.16 (1H, dd, J 5.2, 3.1, C(2)H),
4.25–4.39 (1H, m, C(3)H), 5.68 (1H, d, J 9.6, NH); dC (100 MHz,
CDCl3) 23.5 (COMe), 25.2, 26.8, 28.8 (C(4), C(5), C(6)), 28.1 (CMe3),
32.5 (C(7)), 45.0 (C(8)), 51.0 (C(3)), 73.0 (C(2)), 83.6 (CMe3), 170.0,
172.1 (C(1), COMe); m/z (ESI+) 332 ([M(37Cl)+Na]+, 32%), 330
Step 2: The residue from the previous step was dissolved in 6.0
M aq HCl (19 mL) and the resultant mixture was stirred at 100 °C
for 3 h then allowed to cool to rt. CH2Cl2 (20 mL) was added and
the resultant solution was washed with 1.0 M aq HCl (2 ꢂ 20
mL). The combined aqueous layers were concentrated in vacuo.
Purification via ion-exchange chromatography (Dowex 50WX8-
100, eluent 1.0 M aq NH4OH) gave 17 as a white solid (448 mg,
([M(35Cl)+Na]+, 100%); HRMS (ESI+) C14H2637ClNNaO4 ([M(37Cl)+Na]+)
+
requires 332.1413; found 332.1408; C14H2635ClNNaO4 ([M(35Cl)+Na]+)
89%, >99:1 dr); mp 181.5–182.5 °C; ½a D25
ꢀ4.9 (c 0.5 in MeOH); mmax
ꢃ
+
requires 330.1443; found 330.1458.
3427 (br, OAH, N–H), 1615 (C@O); dH (500 MHz, MeOH-d4) 1.39–
1.65 (4H, m, C(5)H2, C(6)H2), 1.74–1.80 (2H, m, C(4)H2), 1.81–
1.87 (2H, m, C(7)H2), 3.37 (1H, td, J 7.0, 3.1, C(3)H), 3.58 (2H, t, J
6.6, C(8)H2), 3.96 (1H, d, J 3.1, C(2)H); dC (125 MHz, MeOH-d4)
25.8, 27.7 (C(5), C(6)), 30.8 (C(4)), 33.5 (C(7)), 45.5 (C(8)), 55.2
(C(3)), 71.7 (C(2)), 177.4 (C(1)); m/z (ESI+) 212 ([M(37Cl)+H+, 32%),
4.1.17. (R,R)-2-Hydroxy-3-amino-8-chlorooctanoic acid [(R,R)-
chloro-ahoa] 20
A solution of 45 (224 mg, 0.729 mmol, >99:1 dr) in 6.0 M aq HCl
(7.0 mL) was stirred at 100 °C for 3 h, then concentrated in vacuo.
Please cite this article in press as: Davies, S. G.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.09.022

8
S. G. Davies et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
210 ([M(35Cl)+H]+, 100%); HRMS (ESI+) C8H1737ClNO3 ([M(37Cl)+H]+)
pyridine (4.7 mL) at 0 °C. The resultant mixture was allowed to
warm to rt and stirred at rt for 18 h. The reaction mixture was
the diluted with H2O (10 mL) and EtOAc (10 mL), and the aqueous
later was extracted with EtOAc (2 ꢂ 10 mL). The combined organic
extracts were washed with brine (20 mL), then dried and concen-
trated in vacuo. Purification via flash column chromatography (elu-
ent 30–40 °C petroleum ether/EtOAc, 94:6) gave 52 as a colourless
+
+
requires 212.0862; found 212.0870; C8H1735ClNO3 ([M(35Cl)+H]+)
requires 210.0891; found 210.0899.
4.1.20. tert-Butyl (R,R,R)-2-acetoxy-3-[N-benzyl-N-a-(methyl-
benzyl)amino]-8,8-dichlorooctanoate 48
Ac2O (0.47 mL, 5.0 mmol) and DMAP (6 mg, 0.05 mmol) were
added to a stirred solution of 34 (246 mg, 0.497 mmol) in pyridine
(2.1 mL) at 0 °C. The resultant mixture was allowed to warm to rt
and stirred at rt for 18 h. The reaction mixture was the diluted with
H2O (5 mL) and EtOAc (5 mL), and the aqueous later was extracted
with EtOAc (2 ꢂ 10 mL). The combined organic extracts were
washed with brine (35 mL), then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30–40 °C
petroleum ether/EtOAc, 98:2) gave 48 as a colourless oil (261 mg,
oil (551 mg, 92%, >99:1 dr); ½a D25
ꢃ
ꢀ1.5 (c 1.0 in CHCl3); mmax 1741
(2 ꢂ C@O); dH (400 MHz, CDCl3) 1.21 (3H, d, J 7.0, C(
a)Me),
1.38 (9H, s, CMe3), 1.12–1.56 (6H, m, C(4)H2, C(5)H2, C(6)H2),
1.92 (3H, s, COMe), 1.96–2.05 (2H, m, C(7)H2), 3.17–3.23 (1H, m,
C(3)H), 3.82–3.84 (2H, m, NCH2Ph), 4.05 (1H, q, J 7.0, C(
4.73–4.81 (1H, m, C(2)H), 5.58 (1H, t, J 6.1, C(8)H), 7.12–7.35
(10H, m, Ph); dC (100 MHz, CDCl3) 20.2 (COMe), 20.8 (C( )Me),
26.0, 26.1, 28.6 (C(4), C(5), C(6)), 28.1 (CMe3), 43.5 (C(7)), 50.9
(NCH2Ph), 59.3 (C(3)), 60.9 (C( )), 73.6 (C(2)), 75.9 (C(8)), 82.3
a)H),
a
98%, >99:1 dr); ½a D25
ꢃ
ꢀ1.8 (c 1.0 in CHCl3); mmax 1742 (C@O); dH
a
(400 MHz, CDCl3) 1.11 (3H, d, J 7.0, C(
a
)Me), 1.30 (9H, s, CMe3),
(CMe3), 126.6, 127.2, 127.6, 128.1, 128.2, 128.4 (o,m,p-Ph), 142.2,
143.9 (i-Ph), 168.7, 170.5 (C(1), COMe); m/z (ESI+) 540 ([M(37Cl2)+H]+,
10%), 538 ([M(35Cl,37Cl)+H]+, 64%), 536 ([M(35Cl2)+H]+, 100%);
1.17–1.78 (6H, m, C(4)H2, C(5)H2, C(6)H2), 1.87–2.07 (2H, m, C(7)
H2), 1.94 (3H, s, COMe), 3.18–3.26 (1H, m, C(3)H), 3.48 (1H, d, J
)H), 4.12 (1H, d, J 15.5,
NCHAHBPh), 4.88–5.00 (1H, m, C(2)H), 5.56 (1H, t, J 6.1, C(8)H),
7.12–7.39 (10H, m, Ph); dC (100 MHz, CDCl3) 18.6 (COMe), 21.3
HRMS (ESI+) C29H4037Cl2NO4 ([M(37Cl2)+H]+) requires 540.2270;
+
15.5, NCHAHBPh), 3.82–3.89 (1H, m, C(
a
found 540.2256; C29H4035Cl37ClNO4 ([M(35Cl,37Cl)+H]+) requires
+
+
538.2299; found 538.2299;
C
29H4035Cl2NO4 ([M(35Cl2)+H]+)
(C(a)Me), 22.0, 26.0, 26.2 (C(4), C(5), C(6)), 28.4 (CMe3), 43.8 (C(7)),
requires 536.2329; found 536.2327.
50.8 (NCH2Ph), 57.9 (C(3)), 60.2 (C(
a
)), 73.2 (C(2)), 73.9 (C(8)),
82.2 (CMe3), 126.6, 127.2, 127.7, 127.8, 127.9, 128.4 (o,m,p-Ph),
142.8, 144.1 (i-Ph), 168.8, 170.6 (C(1), COMe); m/z (ESI+) 540
([M(37Cl2)+H]+, 10%), 538 ([M(35Cl,37Cl)+H]+, 64%), 536 ([M(35Cl2)+H]+,
4.1.23. (2S,3R)-2-Hydroxy-3-amino-8,8-dichlorooctanoic acid
[(2S,3R)-dichloro-ahoa] 18
Step 1: A solution of NaBrO3 (235 mg, 1.56 mmol) in H2O (5.0
mL) was added to a stirred solution of 52 (279 mg, 0.521 mmol,
>99:1 dr) in EtOAc (7.0 mL) at rt and the resultant mixture was
stirred at rt for 10 min. A solution of Na2S2O4 (227 mg, 1.302
mmol) in H2O (9.4 mL) was added dropwise at rt over 5 min then
the reaction mixture was stirred at rt for 4 h. EtOAc (10 mL) was
added and the resultant mixture was washed with satd aq Na2S2-
O3 (10 mL). The aqueous layer was extracted with EtOAc (2 ꢂ 10
mL) and the combined organic extracts were washed with brine
(35 mL), then dried and concentrated in vacuo.
100%); HRMS (ESI+) C29H4037Cl2NO4 ([M(37Cl2)+H]+) requires
+
+
540.2270; found 540.2252;
C
29H4035Cl37ClNO4 ([M(35Cl,37Cl)+H]+)
requires 538.2299; found 538.2291; C29H4035Cl2NO4 ([M(35Cl2)+H]+)
requires 536.2329; found 536.2326.
+
4.1.21. (R,R)-2-Hydroxy-3-amino-8,8-dichlorooctanoic acid
[(R,R)-dichloro-ahoa] 21
Step 1: A solution of NaBrO3 (179 mg, 1.29 mmol) in H2O (4.0
mL) was added to a stirred solution of 48 (212 mg, 0.396 mmol,
>99:1 dr) in EtOAc (5.4 mL) at rt and the resultant mixture was
stirred at rt for 10 min. A solution of Na2S2O4 (172 mg, 0.991
mmol) in H2O (7.2 mL) was added dropwise at rt over 5 min then
the reaction mixture was stirred at rt for 4 h. EtOAc (10 mL) was
added and the resultant mixture was washed with satd aq Na2S2-
O3 (10 mL). The aqueous layer was extracted with EtOAc (2 ꢂ 10
mL) and the combined organic extracts were washed with brine
(35 mL), then dried and concentrated in vacuo.
Step 2: The residue from the previous step was dissolved in 6.0
M aq HCl (5 mL) was stirred at rt for 80 h, then concentrated in
vacuo. Purification via ion-exchange chromatography (Dowex
50WX8-100, eluent 1.0 M aq NH4OH) gave 18 as a white solid
(66 mg, 52%, >99:1 dr); mp 209.5–210.5 °C; ½a D25
ꢀ7.7 (c 0.5 in
ꢃ
MeOH); mmax 3395 (br, OAH, NAH), 1617 (C@O); dH (500 MHz,
D2O) 1.26–1.52 (2H, m, C(5)H2), 1.53–1.69 (2H, m, C(6)H2),
1.76 (2H, ddd, J 13.9, 7.0, 6.8, C(4)H2), 2.10–2.23 (2H, m, C(7)H2),
3.44 (1H, td, J 7.0, 3.8, C(3)H), 4.06 (1H, d, J 3.8, C(2)H), 5.97
(1H, t, J 6.0, C(8)H); dC (125 MHz, D2O) 23.5 (C(5)), 24.9 (C(6)),
28.6 (C(4)), 42.1 (C(7)), 53.8 (C(3)), 70.6 (C(2)), 73.8 (C(8)), 176.8
(C(1)); m/z (ESI+) 248 ([M(37Cl2)+H]+, 10%), 246 ([M(35Cl,37Cl)+H]+,
Step 2: The residue from the previous step was dissolved in 6.0 M
aq HCl (5 mL) and the resultant mixture was stirred at rt for 18 h,
then concentrated in vacuo. Purification via ion-exchange chro-
matography (Dowex 50WX8-100, eluent 1.0 M aq NH4OH) gave
21 as a white solid (45 mg, 47%, >99:1 dr); mp 196–197 °C; ½a D25
ꢃ
64%), 244 ([M(35Cl2)+H]+, 100%); HRMS (ESI+) C8H1637Cl2NO3
+
([M(37Cl2)+H]+) requires 248.0443; found 248.0443; C8H1635Cl37ClNO3
+
+32.7 (c 0.5 in MeOH); mmax 3401 (br, OAH, NAH), 1596 (C@O);
dH (500 MHz, D2O) 1.26–1.47 (2H, m, C(5)H2), 1.47–1.51 (2H, m,
C(6)H2), 1.51–1.63 (2H, m, C(4)H2), 2.14–2.18 (2H, m, C(7)H2), 3.49
(1H, ddd, J 8.6, 5.7, 3.5, C(3)H), 4.12 (1H, d, J 3.5, C(2)H), 5.91 (1H,
t, J 6.0, C(8)H); dC (125 MHz, D2O) 23.9 (C(5)), 24.9 (C(6)), 26.9
(C(4)), 42.2 (C(7)), 53.8 (C(3)), 71.5 (C(2)), 73.9 (C(8)), 176.6 (C(1));
m/z (ESIꢀ) 246 ([M(37Cl2)ꢀH]ꢀ, 10%), 244 ([M(35Cl,37Cl)ꢀH]ꢀ,
64%), 242 ([M(35Cl2)ꢀH]ꢀ, 100%); HRMS (ESIꢀ) C8H1437Cl2NOꢀ3
([M(37Cl2)ꢀH]ꢀ) requires 246.0297; found 246.0293; C8H1435Cl37ClNOꢀ3
([M(35Cl,37Cl)ꢀH]ꢀ) requires 244.0327; found 244.0323;
C8H1435Cl2NO4ꢀ ([M(35Cl2)ꢀH]ꢀ) requires 242.0356; found 242.0358.
([M(35Cl,37Cl)+H]+) requires 246.0472; found 246.04737;
+
C8H1635Cl2NO4 ([M(35Cl2)+H]+) requires 244.0502; found 244.0504.
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A
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