Formal synthesis of an unusual amino acid component of cyclosporin, involving stereocontrolled nucleophilic 1,4-addition

Article abstract of DOI:10.1016/S0957-4166(97)00164-X

A syn-(2R)-amino-1,3,4-butanetriol derivative, readily available from D-isoascorbic acid, was utilized for the synthesis of MeBmt found in the immunosuppressive undecacyclopeptide cyclosporin. This new strategy involves diastereoselective nucleophilic 1,4-addition of lithium dimethylcuprate to a chiral α,β-unsaturated aldehyde, and elaboration of the terminal double bond, by Takai or Wittig method for the MeBmt or its 6Z-isomer, respectively.

Full text of DOI:10.1016/S0957-4166(97)00164-X

Tetrahedron: Asymrnetr~, Vol. 8. No. 10, pp. 1649-1659. 1997
~) 1997 Elsevier Science Ltd. All rights reserved.
Printed in Great Britain
) Pergamon
~
PII: S0957-4166(97)00164-X
0957-4166/97 $17.00 + 0.00
Formal synthesis of an unusual amino acid component of
cyclosporin, involving stereocontrolled nucleophilic 1,4-addition
Arounarith Tuch, Michrle Sanirre, Yves Le Merrer * and Jean-Claude Depezay
Universit6 Ren6 Descartes, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, associ6
au CNRS, 45, rue des Saints-Pbres, 75270 Paris Cedex 06, France
Abstract:
A syn-(2R)-amino-l,3,4-butanetriol derivative, readily available from D-
isoascorbic acid, was utilized for the synthesis of MeBmt found in the immunosuppressive
undecacyclopeptide cyclosporin. This new strategy involves diastereoselective nucleophilic
1,4-addition of lithium dimethylcuprate to a chiral cx,[3-unsaturated aldehyde, and
elaboration of the terminal double bond, by Takai or Wittig method for the MeBmt or its
6Z-isomer, respectively. (~) 1997 Elsevier Science Ltd
(2S,3R,4R,6E)-3-Hydroxy-4-methyl-2-methylamino-6-octenoic acid (MeBmt)1 is the unique C-9
amino acid constituent of the immunosuppressive undecacyclopeptide cyclosporin. MeBmt shows no
biological activity, however, modification of the MeBmt moiety in cyclosporin greatly affects the
immunosuppressive activity of this therapeutic agent. For example: modification at C-3 by acylation,2
alkylation, 3 substitution by a thiol4 of the hydroxyl group, modification at C-4 by demethylation,5
methylation,5 epimerization,5'6 or modification of the carbon chain,2'7"8 exhibits alter incorporation
into the undecacyclopeptide, a lower immunosuppressive activity relative to the peptide. However,
isomerization of the ,5-6 double bond (6Z-MeBmt)8'9 shows no loss of cyclosporin's activity.
Since the first 24-step synthesis described by Wenger from L-(+)-diethyl tartrate, l° several synthetic
routes have been reported which involve three main strategies: transformation of chiral building
block (D-glucose,l I D-serine,12 L-glutamic acid,13 2-deoxy-D-ribosel4), aldolization reactions, 15 or
regioselective opening of chiral epoxides.16
As part of our continuing investigations designed to explore the employment of the versatile syn-2R-
amino-1,3,4-butanetrioi derivative 1, easily obtained on a multigram scale from D-isoascorbic acid,17
we have recently developed efficient synthetic procedures for the synthesis of natural aminodiol, 17
3-amino-4-hydroxyazepane and 3-amino-2-hydroxyacids. 18 Now, we would like to demonstrate that
this highly functionalized enantiopure chiral building block 1 is a good precursor for MeBmt and
its 6Z-isomer. The key steps of our approach involve the asymmetric 1,4-addition of a methyl group
to the cx,[3-ethylenic aldehyde 2, and subsequent elaboration of the terminal (E) or (Z) double bond
(Scheme 1).
Althought the chemical outcome of conjugate additions to enoates or enones that bear y-alkyl, 19
)¢-alkoxy 2° or y-amino2! substituents has been intensively investigated, only a few examples of such
additions of y-oxido-substituted enal have ben described. 22
Swern oxidation23 of the free primary alcohol function of 1 (Scheme 2) into aldehyde followed
by in situ Wittig reaction with formyimethylene triphenylphosphorane afforded the ot,13-ethylenic
aldehyde 218 in 91% overall yield (E configuration exclusively). Addition of lithium dimethylcuprate
to 224 at - 5 0 ° C led to a mixture of diastereomers 3a and 3b in 72% yield in a 80/20 ratio. After
flash chromatography separation, each stereomer 3a and 3b was subsequently transformed into the
corresponding azepane 8a and 8b, to determine the configuration of the newly created asymmetric
carbon by NMR experiments.
* Corresponding author. Email: lemerrer@bisance.citi2.fr
t649

1650
A. TUCH et al.
OH
O
~
~
/
C
O
H
OHC
H
O
-
- O~ T B D P S
~ O T B D P S
/
NHMe
MeBmt
O/~NBoc
j_
O / ~ B o c
_ ~ ~
[ carbonchain elongation ]
]
,
COOH
~
• asymmetric IA-addition
• Wittig type reaction
N-methylation
-
NHMe
6Z-MeBmt
•
Scheme 1.
;Coc
.
.
1
2
3a+3b (80/20)
Scheme 2. a) (COC1)2, DMSO, NEt3, CH2CI2 then Ph3P=CH~CHO, CH2C12, 24h (91%). b) Me2CuLi, Et20, -50°C (72%).
The azepane formation (Scheme 3) was accomplished, according to analogous described
procedures 18,25 by reduction of the aldehyde and activation of the free hydroxyl group with triflic
anhydride and substitution with N,N'-tetramethylguanidinium azide, transformation of the azido
group into the N-benzyl carbamate, and subsequent cyclization after deprotection and mesylation of
the primary alcohol function.
( - - oToPs e. Z ?NZ
a
..
3a (or 3b)
(
4 (a or b) X = OH
8a (or 8b)
bc~ 5 (aorb) X =N3
,k 6 (a or b) X = NH2
dL7(aorb) X=NHZ
Z= PhCH2OCO
Scheme 3. a) H2, Ni Raney, EtOH. b) (CF3SO2)20 CHCI3, 2,6-1utidine then (Me2N)2CNH2+ N3- (48%) from 3a or 3b.
c) H2, Pd/C (10%), THF. d) PhCH2OCOCI, NaOH, 1,4-dioxane (57%) from 5a or 5h e) i: nBu4NF, THF; ii: CH3SO2CI,
Et3N, CH2C12; iii: tBuOK, THF (50%).
2D NOESY diagram of 8a26 with I H NMR spectrum (Figure 1) showed, notably, by cross signals
of the methyl group (0.76 ppm) with H3 (3.75 ppm), and H5 (2.10 ppm) with H4 (3.94 ppm), a cis-
relationship between Me/I-I3 and H4/H5, thus an R configuration for C5 of the azepane 8a. Likewise,
2D NOESY diagram of 8b showed, notably, by cross signals of methyl (0.95 ppm) with H4 (3.90
ppm), a c i s - r e l a t i o n s h i p between Me/H4, thus an S configuration for C5 of the azepane 8b.
Since the transformation of 3a into 8a, or 3b into 8b, was carried out with retention of configuration,

An unusual amino acid component of cyclosporin
1651
1
3 a
(~7\ ,NBoc
8a
H , , . ~ N )Z
3b
,.
2
'''H
~..._. H ON NBoc
8b
\
Figure 1. Main observed nOe (1H NMR, 2D NOESY, 250 MHz, C6D6, 65°C) and stereoview of the minimized conformation
from molecular dynamic simulations26 of azepanes 8a and 8b.
these results showed that the absolute configuration of the newly created asymmetric carbon atom was
R for the major diastereomer 3a, and S for the minor one 3b.
For a mechanistic point of view outcome of the addition of dimethylcuprate to enal 2 can be explained
by a modified Felkin-Anh model for the transition state with a carbon-carbon bond formation anti to
the ~,-alkoxy group:
®Nu
, ,
BocN
~
H
Having in hand the major stereomer 3a possessing the R configuration at C-Me, we proceeded to
the synthesis of MeBmt and its 6Z-isomer (Scheme 4).
For the transformation of the aldehyde 3a into the olefin E-9, the Takai method,27 by treatment
with 1,1-diiodoethane in presence of chromium(II) chloride in excess, revealed to be the best one to
have a good control of the stereochemistry (87% yield, E/Z>95%, IH NMR analysis).28
On the other hand, Wittig reaction on the aldehyde 3a with the ylide derived from ethyltriphenyl-
phosphonium bromide, by treatment with butyllithium in diluted solution of THF at -78°C, afforded
only the olefin Z-9 (75% yield, Z/E>95%, IH NMR analysis).
The final transformations were then carried out on each isomer (E-9 and Z-9). Deprotection of the
silylether followed by Swern oxidation of the primary alcohol to aldehyde, with further oxidation
to carboxylic acid in the presence of sodium chlorite and sulfamic acid, and esterification led to
the methyl ester E-11 or Z-11 in respectively 61% or 65% overall yield. N-Methylation was readily

1652
A. TUCH et al.
C_H3
CH~
CH3
~
O H c ~ O T B D P S
R
~
V
CO2CH3
R~
d
. ~
a (or b)
O/,,~Boc
R2
O ~ NB°c
3a
/
E-9 R ~=Me,Rz=H,P=TBDPS
E-11 W = M e , RZ=H
c ~ Z-9 RI=H,Rz=Me,P=TBDPS
E-10 W= Me, R2= H, P= H
Z-ll W= H, RZ= Me
c
Z-10 W=H, RZ=Me, P= H
el
CH3 NHCH3
CH~
CH3
•
R
-
CO2CH3
R
O~CH3
CO2H
R2
OH
h
f
"I
-
P
q
R2
HO
NH2.
CF3CO2H
y
MeBmt
R~ = Me, R2= H,
O
E-12 W =Me, R2= H
Z-12 W = H, R2= Me
E-13 W=Me, R2= H,P=H
6Z-isomer RI = H, R2= Me,
ggl Z-13 W=H, R2=Me, P=H
E-14 RI= Me, RZ= H, P = Me
Z-14 RI=H,Rz=Me,P=Me
Scheme 4. a) CH3CHI2, CrCl2, THF (87%), E/Z>_95% b) Ph~P+CH2CH3 Br-, BuLi, THE -78°C (75%) Z/E>_95%.
c) nBu4NF, THF (96% for Z-10 and 90% for E-10). c) i: (COCt)2, DMSO. NEt3, CH2C12: ii: NaCIO2/NH2SO3H, 1,4-
dioxane-H20; iii: CH2N2 (61% overall from E-1O and 65% from Z-10). e) CF3COOH-H20. f) CI3COCOC1, CH2CI2/NEt3
I/I (61% from E-t1 and 55% from Z-t1). g) Mel, Ag20, DMF (86%). h) see ref.10
performed by acidic hydrolysis of both oxazolidine and the N-carbamate protecting group leading to E-
12 or Z-12, followed by formation of the oxazolidinone using trichloromethyl chloroformate (TCF)29
and subsequent methylation with methyliodide in presence of silver(I) oxide. 3° E-14 is thus obtained
with 53% overall yield from E-11, and Z-14 with 47% overall yield from Z-11. Comparison of the
physical and spectroscopic data of E-14 and Z-14 with those described 15b'f were in good agreement.
They could be easily converted into the final amino acid, MeBmt or its 6Z-isomer, respectively by
hydrolysis according to the procedure of Wenger.10
In summary, we have presented here a practical synthesis of MeBmt present in the structure of im-
munosuppressive cyclosporin and its Z-isomer, via the enantiopure syn-2R-1,3,4-butanetriol derivative
prepared from D-isoascorbic acid. The key steps of this new strategy involve the diastereoselective
nucleophilic 1,4-addition of lithium dimethylcuprate to c~,13-ethylenic aldehyde with preponderance
of anti-orientated C-methyl product, and subsequent elaboration of the terminal double bond by the
Takai or Wittig method. Our current efforts involve the study of this asymmetric 1,4-addition, and the
obtention of other unusual amino acids•
E x p e r i m e n t a l s e c t i o n
Prior to use, tetrahydrofuran (THF) and diethylether (Et20) were distilled from sodium-
benzophenone and dichloromethane (CH2CI2) from P205. CH2Ci2 and ethyl acetate (EtOAc) were
filtered on K2CO3 prior to use. 1H NMR (250 MHz) and 13C NMR (62,9 MHz) spectra were
recorded on a Bruker AM 250. Chemical shifts are reported in 8 (ppm)31 and coupling constants
are given in Hertz. High Resolution Mass Spectra were recorded in Service de Spectrom6trie
de Masse, Universit6 Pierre et Marie Curie. Specific rotations were measured on a Perkin Elmer
241C polarimeter with sodium (589 nm) lamp at 20°C. All reactions were carried out under argon

1653
An unusual amino acid component of cyclosponn
atmosphere, and were monitored by thin-layer chromatography with Merck 60F-254 precoated silica
(0.2 ram) on glass. Chromatography was performed with Merck Kieselgel 60 (200-500 lam) or
60H (5-40 lain). Spectroscopic (IH and 13C NMR, MS) and/or analytical data were obtained using
chromatographically homogeneous samples.
Addition of Mee CuLi on o¢, [3-ethylenic aldehyde 2
To a suspension of cuprous iodide (3.49 g, 18.3 mmol) in ether was dropwise added methylithium
(1.56 M in ether, 23.5 mL, 36.7 mmol). After stirred for 45 min at -30°C, the reaction mixture was
cooled at -50°C and the aldehyde 218 (3.20 g, 6.11 mmol) in ether (104 mL) was added. The mixture
was warmed at 0°C and 50 mL of brine was added. After extraction with ether (3 ×60 mL), the organic
layers were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography of the residue
(cyclohexane/EtOAc 9/1) afforded 1.97 g of 3a (60%, Rf 0.2) and 0.40 g of 3b (12%, Rf 0.3).
(4R~5R)~3-N-tert-But3~l~xycarb~ny~-4-tert-bu~ldipheny~si~y~xynwthyl-5[( ~''R)- ~''-methyl propan-
3" -all-2, 2-dimethyl- 1,3-oxazolidine 3a
[O~]D -19 (c 1.18, CH2CI2). IH NMR (C6D6. 65°C) ~: 9.47 (IH, dd, H-3", J3,,2,'a=l,5 Hz,
J3,, 2,,b=2 Hz), 7.84-7.16 (10H, 2m, Ph), 4.54-3.83 (4H, m, H-5,4,1'), 2.44 (1H, ddd, H-2"a,
J2,,a.2,,b=-16 Hz, J2,,a.3,,=l.5 Hz, J2,,a.l,,=4 Hz), 2.19-2.07 (1H, m, H-I"), 1.98 (1H, ddd, H2,,b,
J2,,b,l,,=8 Hz, J2,,a,2,,b=- 16 Hz, J2,,b,3,,=2 Hz), 1.60, 1.55 (6H, 2s, CMe2), 1.36 (9H, 2, OtBu), 1.15
(9H, s, SitBu), 0.87 (3H, d, CH3, JCH3,H I" =6.5 Hz). 13C NMR (C6D6, 65°C) 8:199.9 (C-3"), 151.9
(NCO2), 136.1, 133.9, 130.1, 128.2 (Ph), 94.7 (C-2), 81.9 (C-5), 79.7 ((CH3)3CO), 63.8 (C-I'), 62.1
(C-4), 47.0 (C-2"), 32.8 (C-I"), 28.5(OCMe3), 28.1, 27.6 (CMe2), 27.2 (Me3CSi), 19.5 (Me3CSi),
17.5 (CH3). HMRS for C23H28NO5Si (M+-CsHIT), calcd 426.1737, found 426.1736.
(4R~5R)-3-N-tert-Bu~l~x3~carb~nyl-4-tert-bu~ldiphenylsily~xymethyl-5-[(~S'')-~''-methyl propan-
3" -al]-2,2-dimethyl- 1,3-oxazolidine 3b
[0C]D --10 (c 1.08, CH2C12). IH NMR (C6D6, 65°C) 6:9.42 (1H, dd, H-3", J3,'2"a=2 Hz,
J3",2,'b=1.6 Hz), 7.92-7.18 (1OH, 2m, Ph), 4.33-3.74 (4H, m, H-5,4,1'), 2.45-2.28 (2H, m, H- 1",2"a),
2.07-1.87 (1H, ddd, H-2"b, J2,,b.3,,=l.6 Hz, J2"a,2"b=-15 Hz, J2,,b.l,,=7 Hz), 1.60, 1.57 (6H, 2s,
CMe2), 1.36 (9H, s, OtBu), 1.15 (9H, s, SitBu), 0.87 (3H, d, CH3, JCH3,HI"=6.4 Hz). 13C NMR
(C6D6, 65°C) 8:199.6 (C-3"), 152.0 (NCO2), 136.1,133.9, 130.1, !28.1 (Ph), 94.5 (C-2), 80.7 (C-5),
79.7 (OCMe3), 63.4 (C-I'), 60.0 (C-4), 48.4 (C-2"), 31.1 (C-I"), 28.5 (OCMe3), 28.3, 27.8 (CMe2),
27.2 (Me3CSi), 19.5 (Me3CSi), 14.5 (CH3). Anal. calcd for C31H45NO5Si: C, 68.98; H, 8.40; N,
2.59. Found: C, 68.86; H, 8.36; N, 2.48.
(4R~5R )-3-N-tert-Butyl~©~carb~nyl-4-tert-but3'ldiphenylsilyl~x3~methyl-5-[ (~''R)- y'-hydr~©~-1''-
methylpropyl]-2, 2-dimethyl- 1,3-oxazolidine 4a
A solution of 3a (202 mg, 0.37 mmol) in EtOH (6 mL) was stirred for 4 h under hydrogen in
the presence of a catalytic amount of Raney nickel (40 mg, P=3 atm). After filtration through a
celite pad and concentration in vacuo, 133 mg (66%) of 4a was obtained after flash chromatography
(cyclohexane/EtOAc 8/2 Rf 0.2). 1H NMR (CDC13) 8:7.70-7.30 (10H, 2m, Ph), 4.08-3.50 (6H, m,
H-5,4,3",1"), 2.00-1.20 (18H, m, H-2",I",CMe2, OtBu), 1.03-0.80 (12H, m, SitBu,CH3).
(4•L5R)-3-N•tert•Butyl•xycarb•nyl-4-tert-butyldiphenylsi•yl•©•methyl•5•[(
methylpropyl]-2, 2-dimethyl- 1,3-oxazolidine 4b
•••S)•3•••hydr•xy••••-
The reaction of the aldehyde 3b (161 mg, 0.30 mmol) under the above experimental conditions
furnished after flash chromatography (cyciohexane/EtOAc 8/2, Rf 0.2) 123 mg (76%) of 4b. IH NMR
(CDCI3) 8:7.70-7.25 (10H, 2m, Ph), 4.20-3.50 (6H, m, H-5,4,3",1'), 1.95-1.20 (18H, m, H-2",l"
CMe2, OtBu), 1.10---0.85 (12H, m, SitBu, CH3).

1654
A. TtCH et al.
(4R~5R)-3~N-tert~But);l~xycarb~nyl~4-tert-bu~ldiphenylsilyl~xymethyl-5-[(
carbonyl- l"-methylpropyl]-2,2-dimethyl- l,3-oxazolidine 7a
~R)~3~N~benzyl~`~-
At -50°C, to a stirred solution of 4a (125 mg, 0.23 mmol) in CHCI3 was added trifluoromethane-
sulphonic anhydride (47 laL, 0.28 mmol), then after 5 rain, 2,6-1utidine (32 laL, 0.28 mmol) and after
30 min tetramethylguanidiniumazide (TMGA 109 mg, 0.69 mmol). After stirring for 1 h at -50°C,
the mixture was concentrated and filtered on pad of silice with EtOAc/cyclohexane (v/v 1/9) to discard
the by-products. 94 mg of 5a were obtained (72%).
A solution of 5a (94 mg, 0.17 mmol) in THF (1 mL) was stirred under hydrogene in the presence
of a catalytic amount of palladium on charcoal 10% (9 mg). After filtration through a celite pad and
concentration in vacuo the crude amine was used without purification in the next step. To a solution of
the amine in dioxane (1 mL), at 0°C, in the presence of NaOH (3 N, 166 laL, 0.50 mmol) was added
dropwise benzylchloroformate (28 laL, 0.20 nmol). After stirring for 45 rain the reaction mixture was
poured into a saturated solution of ammonium chloride (2 mL) and extracted with CH2C12 (3x3 mL).
The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give after
chromatography (cyclohexane/EtOAc 8/2 Rf 0.3) 46 mg (57%) of 7a. I H NMR (CDCI3) 6:7.70-7.30
(15H, 2m, Ph), 5.07 (2H, s, CH2Ph), 4.75 (1H, brs, NH), 4.0(O3.10 (H-5,4,3",1'), 2.00-1.20 (18H,
m, H-2",I",CMe2,OtBu), 1.10-0.80 (12H, m, SitBu,CH3).
( 4R~5R)-3~N~tert-Buty~x3~carb~nyl-4~tert-bu~dipheny~si~yl~xymethyl-5~[( ~ S )-3~N-benzy~x3~-
carbonyl- l"-methylpropyl]-2,2-dimethyl- l,3-oxazolidine 7b
The reaction of the alcohol 4b (123 mg, 0.23 mmol) under the above experimental conditions
furnished after purification 68 mg (53%) of 5b.
The reaction of the azido 5b (68 mg, 0.12 mmol) under the above experimental conditions furnished
after purification (cyclohexane/EtOAc 8/2, Rf 0.3) 25 mg (31%) of 7b. 1H NMR (CDC13) ~i: 7.70-7.30
(15H, 2m, Ph), 5.10 (2H, s, CH2Ph), 4,74 (IH, brs, NH), 4.10-3.10 (6H, m, H-5, 4,3",1'), 2.10-0.80
(30H, m, H-2",l", CMe2, OtBu, SitBu, CH3).
( 3R~4R~5R)-3-N-Benzyl~xycarb~nyl-3'4-[ 3~-N-tert-bu~l~.carb~nyl-2'~2'-dimethyl- l',3'-oxazolid-
inyl]-azepane 8a
At 20°C to a stirred solution of silylether 7a (64 mg, 0.10 mmol) in THF (2 mL) was added
dropwise n-tetrabutylammonium fluoride (104 IlL 0.11 mmol, 1M in THF). After stirring for 20 h and
concentration in vacuo, water (1 mL) was added; after extraction with CH2C12 (3 ×2 mL), the combined
organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography of the
residue (EtOAc/cyclohexane 1/1 Rf 0.4) gave 36 mg (88%) of the corresponding alcohol.
To a solution of this alcohol above obtained (36 mg, 0.08 mmol) in CH2C12 (330 laL) in the presence
of NEt3 (17 IlL, 0.10 mmol) was added at 0°C mesylchloride (8 IlL, 0.10 mmol). After stirring for 20
rain, the mixture was poured into water; after extraction with CH2C12 (3×2 mL) the combined organic
layers were dried (Na2SO4), filtered and concentrated in vacuo to give the corresponding mesylate
which was used without purification in the next step.
At 20°C to the crude mesylate in THF (4.2 mL) was added a solution of tBuOK in THF (200 IlL,
0.10 mmol, 0.5 M). After stirring for 2 h, 2 mL of ammonium chloride was added. After extraction
with CH2C12 (3x 3 mL), the combined organic layers were dried (Na2SO4), filtered and concentrated
in vacuo. Flash chromatography of the residue (cyclohexane/EtOAc 8/2 Rf 0.4) gave 19 mg (56%)
of 8a. [O~]D -i15 (c 1.00, CH2C12). IH NMR (C6D6, 65°C) 5:7.35-7.00 (m, 10H, Ph), 5.10 (2H,
AB, CH2Ph, JAB=- 12.4 Hz), 4.34 (IH, dd, H-2a, J2a,2b=- 12.9 Hz, J2a,3=5.3 Hz), 3.94 (1H, dd, H-
4, J3,4=9.3 Hz, J4,5=3.4 Hz), 3.75 (1H, m, H-3), 3.65-3.32 (1H, m, H-2b,7b), 2.78 (IH, m, H-7a)
2.10 (IH, m, H-5), 1.90-1.12 (16H, m, H-6b, CMe2, OtBu), 1.06 (IH, m, H-6a), 0.76 (3H, d, CH3,
JCH3,HS=7 Hz). ]3C NMR (C6D6, 65°C) 5:155.8 (NCO2Bn), 152.5 (NCO2tBu), 94.3 (C-2'), 80.2
(C-5), 79.9 (OCMe3), 67.3 (PhCH2), 54.8 (C-4), 49.5, 42.3, 32.0 (C-2,6,7), 28.5 (OCMe3), 30.8, 26.0
(CMe2), 13.0 (CH3). HRMS for C23H34N205: (M+) calcd 418.2468, found 418.2466.

An unusual amino acid component of cyclosporin
1655
(3R• 4R•5S )-3-N-Benzyl•xycarb•nyl- 3• 4-[-3'- N-tert-butyl•xycarb•nyl-2••2'-dimethyl-
inyl]-azepane 8b
l',3'-oxazolid-
The silylether 7b under the above experimental conditions furnished after flash chromatography
(cyclohexane/EtOAc 8/2 Rf 0.4) 4 mg (30% overall yield) of 8b. [CX]D -83 (c 1.00, CH2C12). 1H
NMR (C6D6, 65°C) 6:7.30-7.00 (5H, m, Ph), 5.12 (2H, AB, PhCH2, JAI3=- 12.5 Hz), 4.30 (1H, m,
H-2a), 4.00-3.40 (5H, m, H-3,4,2b,7b), 2.50 (1H, m, H-7a), 1.75-1.20 (18H, m, CMe2, OtBu, H-5,6),
0.95 (3H, d, CH3, JCH3,H5=6 Hz).
(4R•5R )- 3-N-tert-Butyl•©'carb•nyl-4-tert-butyldiphenylsilyl•xymethyl-5-[
pent-3"-enyl]-2,2-dimethyl-l,3-oxazolidine E-9
(•' 'R•y 'E)-• •'-methyl-
To a chromium II chloride suspension (1.10 g, 8.91 mmol) in THF (22 mL) at room temperature
was added a solution of the aldehyde 3a (601 mg, 1.11 retool) and 1,1-diiodoethane (2.24 laL, 2.22
mmol) in THF (3.4 mL). After stirring for 12 h, brine (10 mL) was added; after extraction with
ethylacetate (3x 10 mL) the combined organic layers were dried (Na2SO4), filtered and concentrated
in vacuo. Flash chromatography of the residue (EtOAc/cyclohexane 5/95, Rf 0.4) gave 534 mg (87%)
of E-9. [CX]D - 11 (c 1.00, CH2C12). 1H NMR (C6D6, 65°C) /5:7.88-7.10 (1OH, 2m, Ph), 5.56-5.32
(2H, m, H4,, 3,,), 4.20 (1H, dd, H-5, J5,1,,=3.5 Hz, J5,4=8 Hz), 4.28-3.90 (3H, m, H-4,1'), 2.45 (1H,
m, H-2"a), 1.97 (1H, m, H-2"b), 1.82-1.56 (10H, m, H-I",5", MezC), 1.38 (9H, s, OtBu), 1.17 (9H,
s, SitBu), 0.94 (3H, d, CH3, JCH3,HU=6.7 Hz). 13C NMR (C6D6, 65°C) 6:152.0 (NCO2), 136.1,
134.0, 130.1, 128.1 (Ph), 129.7 (C-3"), 126.6 (C-4"), 94.4 (C-2), 82.2 (C-5), 79.5 (OCMe3), 63.9
(C-I'), 62.1 (C-4), 37.8 (C-I"), 35.6 (C-2"), 28.5 (OCMe3), 28,1, 27.8 (CMe2), 27.2 (Me3CSi), 19.5
(Me3CSi), 17.9 (CH3), 16.5 (C-5"). Anal. calcd for C33H49NO4Si: C, 71.83; H, 8.95; N, 2.54. Found:
C, 71.86; H, 9.04; N, 2.54.
(
4R~5R)-3-N-tert-Butyl~©~carb~nyl-4-tert-butyldipheny~si~yl~xymethyl-5-[( ~''R~3''Z)- ~-methyl-
pent-Y'-enyl]-2, 2-dimethyl- 1,3-oxazolidine Z-9
To a suspension of the ethyltriphenylphosphonium bromide (1.80 g, 4.84 retool) in THF (19 mL) at
-78°C, was dropwise added n-butyllithium (1.4 M in hexane, 3.40 mL); red coloration progressively
appeared. After 2 h stirring, a solution of aldehyde 3a (870 mg, 1.61 mmoi) in THF (16 mL) was
dropwise added. The temperature was then raised to 20°C for 20 h. The reaction mixture was poured
into an ammonium chloride aqueous solution (15 mL) and extracted with CH2C12 (3×30 mL). The
organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by
flash chromatography (cyclohexane/EtOAc 96.5/3.5; Rf 0.3) to give 668 mg (75%) of Z-9. [CX]D --11
(c 1.35, CH2CI2). 1H NMR (C6D6, 65°C) 6:7.84-7.18 (10H, 2m, Ph), 5.61-5.40 (2H, m, H-4",3"),
4.21 (1H, dd, H-5, J5,4=8 Hz, J5,1,,=3.6 Hz), 4.13-3.90 (3H, m, H-4,1'), 2.48 (1H, m, H-2"a), 2.10
(1H, m, H-2"b), 1.84-1.61 (7H, m, H-I", CMe2), 1.56 (3H, d, H-5", J5,,,4,,=6 Hz), 1.38 (9H, s,
OtBu), 1.14 (9H, s, SitBu), 0.94 (3H, d, CH3, JCH3,HI,,=6.4 Hz). 13C NMR (C6D6, 65°C) 8:152.0
(NCO2), 136.0, 134.0, 130.0, 128.1 (Ph), 128.8 (C-3"), 125.3 (C-4"), 94.3 (C-2), 82.2 (C-5), 79.5
(OCMe3), 63.8 (C-I"), 62.2 (C-4), 38.0 (C- 1"), 29.8 (C-2"), 28.5 (OCMe3), 28.3, 27.6 (CMe2), 27.2
(SiCMe3) 19.5 (SiCMe3), 16.5 (CH3), 12.9 (C-5"). Anal. caicd for C33H49NO4Si: C, 71.83; H, 8.95;
N, 2.59. Found: C, 71.78; H, 8.89; N, 2.56.
(4•L 5R)- 3-N-tert-Buty••xycarb•nyl-4-hydr•xymethyl-5-[(
dimethyl- 1,3-oxazolidine E-IO
•''R•3''E )-•''-methyl-pent- 3''•enyl ]-2•2-
To stirred solution of E-9 (454 mg, 0.82 retool) in THF (19 mL) was added dropwise at 20°C n-tetra-
butylammonium fluoride (905 laL, 0.91 mmol, 1M in THF). After stirring for 20 h, water (10 mL) was
added; after extraction with CH2C12 (3x 10 mL) the combined organic layers were dried (Na2SO4),
filtered and concentrated in vacuo. Flash chromatography of the residue (cyclohexane/EtOAc 8/2 Rf
0.3) gave 233 mg (90%) of E-10. M.p.: 60-61°C. [CX]D -3(c 1.05, CH2C12). 1H NMR (C6D6, 65°C)
/5:5.47-5.28 (2H, m, H-4",3"), 3.88 (1H, m, H-4), 3.74-3.65 (2H, m, H-I'), 3.58 (1H, brt, H-5,

J4,5=Js, l,,=6.7 Hz), 2.34 (1H, m, H-2"a), 1.96-1.80 (IH, m, H-2"b), 1.70-1.53 (10H, m, H-I", 5",
CMe2), 1.38 (9H, s, OtBu), 0.84 (3H, d, CH3, JCH3,HI,,=6.8 Hz). 13C NMR 8:153.6 (NCO2), 129.6
(C-3"), 126.7 (C-4"), 94.3 (C-2), 81.5 (C-5), 80.4 (OCMe3), 65.3 (C-I'), 63.6 (C-4), 37.5 (C-I"),
35.6 (C-2"), 28.5 (CMe3), 28.3, 27.1 (CMe2), 17.8 (CH3), 16.0 (C-5").
(4R~5R )-3-N-tert~Butyl~xycarb~ny~-4~hydr~xvmethyl- 5-[(1''R~3'' Z )-1''-methyl-pent- y'-enyl]-2~2-
dimethyl- 1,3-oxazolidine Z-10
The reaction ofthe silylether Z-9 (247 mg, 0.45 mmol) in THF (10 mL) under the above experimental
conditions furnished after chromatography 134 mg (96%) of the alcohol Z-10. M.p. 36-37°C. [Ot]D
+1 (c 1.20, CH2C12), [0(]Hg365 +7 (c 1.20, CH2C12). ]H NMR (C6D6, 65°C) 8:5.57-5.32 (2H, m,
H-4", 3"), 3.94-3.84 (1H, m, H-4), 3.78-2.64 (2H, m, H-I'), 3.59 (IH, brt, H-5, J5,4=J5,1,, =6.5 Hz),
2.35 (1H, m, H-2"a), 2.01 (1H, m, H-2"b), 1.72-1.50 (10H, m, H-I", 5", CMe2), 1.38 (9H, s, OtBu),
0.85 (3H, d, CH3, JCH3,HI"=6.8 Hz). 13C NMR (C6D6, 65°C) 8:153.7 (NCO2), 128.8 (C-3"), 125.3
(C-4"), 94.3 (C-2), 81.6 (C-5), 80.4 (OCMe3), 65.4 (C-I '), 63.7 (C-4), 37.8 (C-I"), 29.8 (C-2"), 28.4
(OCMe3), 28.3, 27.1 (CMe2), 16.0 (CH3), 12.9 (C-5").
(4S•5R)•3•N•tert•Bu•.l•x3•carb•nyl•4•meth•©•carb•nyl•5•[
dimethyl- 1,3-oxazolidine E- I1
•R•3•E)•
••••methyl•pent•
y•••nyl]•2•2•
To a stirred solution of oxalyl chloride (19 laL, 0.22 mmol) in CH2C12 at -78°C was slowly added
DMSO (31 laL, 0.43 mmol). The resulting complex was stirred for 15 min at -78°C prior to the
addition of alcohol E-10 (45 mg, 0.14 mmol) in CH2C12. After 45 min at -65°C, Et3N (120 laL, 0.86
mmol) was added and the temperature was raised to 20°C. After stirring for 1.5 h, Et20 was added
and the salt (Et3NHCI) was removed by filtration through a celite pad. The filtrate was concentrated in
vacuo to give the crude aldehyde which was used without purification in the next step. To a solution
of the aldehyde in a mixture of water-dioxane (v/v 1/3, 7.2 mL) cooled at 0°C were successively
added sodium chloride (26 rag, 0.29 mmol) and sulfamic acid (14 mg, 0.24 mmol). After stirring for
45 min the reaction mixture was poured into brine (3 mL) and extracted with CH2C12 (3>( 10 mL); the
combined organic layers were dried (Na2SO4) and concentrated in vacuo to gave the carboxylic acid.
To the carboxylic acid in methanol (3 mL), diazomethane in ether was added until yellow coloration.
After concentration in vacuo, flash chromatography of the residue (EtOAc/cyclohexane 5/95 Rf 0.3)
gave 30 mg (61%) of E-11. [fX]D -- 13 (c 1.10,CH2C12). ]H NMR (C6D6, 65°C) 8:5.44-5.24 (2H, m,
H-3",4"), 4.40-4.15 (1H, brs, H-4), 3.99 (1H, t, H-5, Js,4=Js, l-=6.7 Hz), 3.40 (3H, s, OCH3), 2.30
(1H, m, H-2"a), 1.94 (1H, m, H-2"b), 1.82-1.50 (10H, m, H-I", 5", CMe2), 1.39 (9H, s, OtBu),
0.90 (3H, d, CH3, JCH3,HI"=6.8 Hz). ]3C NMR (C6D6, 65°C) 8:172.0 (CO2), 151.6 (NCO2), 129.2
(C-3"), 127.0 (C-4"), 95.3 (C-2), 82.2 (C-5), 80.2 (OCMe3), 63.1 (C-4), 51.5 (OCH3), 37.6 (C-I"),
35.6 (C-2"), 28.4 (OCMe3), 27.3, 25.6 (CMe2), 17.8 (CH3), 15.2 (C-5").
(4S,5R)-3-N-tert-Butyloxycarbonyl-4-methoxycarbonyl-5-( l"R,3"Z)- l"-methyl-pent-3"-enyl-2,2-
dimethyl- 1,3-oxazolidine Z-11
The reaction of alcohol Z-10 (97 mg, 0.31 mmol) with oxalyl chloride (40 laL, 0.46 mmol),
dimethyl sulfoxyde (166 laL, 0.93 mmol), triethylamine (258 IlL, 1.86 nmol), then sodium chlorite
(112 mg, 1.24 mmol), sulfamic acid (60 mg, 0.62 mmol), water/dioxane 1/3 (15.5 mL) under the
above experimental conditions furnished after chromatography purification (cyclohexane/EtOAc 95/5,
Rf 0.3) 69 mg (65%) of Z-ll. [a]D - 14 (c 1.24, CH2C12). IH NMR (C6D6, 65°C) 8:5.57-5.29 (2H,
m, H-4", 3"), 4.35-4.16 (1H, brs, H-4), 3.97(1H, t, H-5, J5,1,,=J5,4=6.8 Hz), 3.40 (3H, s, OCH3),
2.28 (IH, m, H-2"a), 2.02 (1H, m, H-2"b), 1.83-1.60 (7H, m, H-I", CMe2), 1.52 (3H, d, H-5",
J5,,,4,,=6.2 Hz) 1.38 (9H, s, OtBu), 0.89 (3H, d, CH3, JCH3, HI ''=6"8 Hz). 13C NMR (C6D6, 65°C) 8:
172.0 (CO2Me), 151.6(NCO2), 128.3 (C-3"), 125.6 (C-4"), 95.4 (C-2), 82.4(C-5), 80.1 (OCMe3),
63.4 (C-4), 51.6 (OCH3), 37.9 (C-I"), 29.8 (C-2"), 28.4 (OCMe3), 27.2, 25.5 (CMe2), 15.2 (CH3),
12.8 (c-5").

An unusual amino acid component of cyclosporin
1657
(4S~5R)-4~Meth~`carb~nyl-5-[ ~'~R~y'E)~'~-methyl~pent- y'-enyl]-2'2-dimethyl-2-~xaz~-lidin~ne
E-13
At 0°C the oxazolidine E-II (61 rag, 0.20 mmol) was stirred for 5 h in trifluoroacetic acid/water
1/1 (2 mL); the mixture was then freeze-dried and the resulting ammonium trifluoroacetate was used
without purification in the next step.
At -20°C to the ammonium trifluoroacetate in CH2CI2/NEt3 (1/1,6 mL) was added trichloromethyl
chloroformate (17 ~L, 0.14 mmol). After stirring for 2 h, water (6 mL) was added. After extraction
with CH2C12 (3×6 mL), the organic extracts were dried (Na2SO4), filtered and concentrated in vacuo.
The residue was purified by flash chromatography (cyclohexane/EtOAc 6/4, Rf 0.2) to give 27 mg
(61%) of E-13. [~x]D +60 (c 1.00, CH2C12). 1H NMR (CDCI3) 6:6.19 (1H, s, NH), 5.56-5.26 (2H,
m, H-4", 3"), 4.46 (1H, dd, H-5, J5,4=4.5 Hz, J5,1,,=5.8 Hz), 4.08 (IH, d, H-4, J4.5=4.5 Hz), 3.78
(3H, s, OCH3), 2.20 (1H, m, H-2"a), 2.00-1.80 (2H, m, H-2"b, 1"), 1.63 (3H, d, H-5", Js,, 4,,=6.0
Hz), 0.94 (3H, d, CH3, JCH3, HI ''=6.4 Hz). 13C NRM (CDCI3) 6:170.9 (C-I'), 158.4 (C-2), 128.1
(C-3"), 127.3 (C-4"), 82.3 (C-5), 56.0 (C-4), 53.0 (OCH3), 37.6 (C-I"), 34.2 (C-2"), 17.9 (CH3),
13.9 (C-5").
(4S, 5R)-4-Methox3,carbonyl-5-[( l "R, 3" Z)- 1" -methyl-pen t-Y' -enyl]-2, 2-dim ethyl-2-oxazolidinone
Z-13
The reaction of the oxazolidine Z-11 under the above experimental conditions furnished the
oxazolidinone Z-13 with 55% yield. [CX]D +74 (c 0.68, CH2C12). IH NMR (CDCI3) 6:5.85 (1H, s,
NH), 5.57 (1H, m, H-4"), 5.31 (IH, m, H-3"), 4.49 (IH, dd, H-5, J5,1,,=6.4 Hz, J5,4=4.4 Hz), 4.10
(IH, d, H-4, J4.5=4.4 Hz), 3.79 (3H, s, OCH3), 2.25 (IH, m, H-2"a), 2.13-1.82 (2H, m, H-2"b, 1"),
1.60 (3H, d, H-5", J5,,.4,,=8 Hz), 0.97 (3H, d, CH3, JCH3, HI ''=6"8 Hz). 13C NMR (CDC13) c5:170.8
(C-I'), 158.4 (C-2), 126.7, 126.5 (C-3", 4"), 82.5 (C-5), 56.2 (C-4), 53.0 (OCH3), 37.6 (C-I"), 28.3
(C-2"), 14.6 (CH3), 12.9 (C-5").
(4S,5R)-4-Metho~,carbonyl-2-N-methyl-5-[( l"R,Y'E)- l"-methyl-pent-3"-enyl]-2,2-dimethyl-2-
oxazolidinone E-14
To the oxazolidinone E-13 (40 mg, 0.18 mmol) and methyl iodide (87 laL, 1.41 mmol) in DMF (1.3
mL) at 20°C, silver oxide (163 mg, 0.70 mmol) was added. After stirring for 20 h in darkness, the
mixture was filtered through celite, and water (4 mL) was added. After extraction with CH2C12 (3×6
mL), the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Flash
chromatography of the residue (cyclohexane/EtOAc 6/4 Rf 0.3) gave 36 mg (86%) of E-14. [OqD +38
(c 1.00, CH2CI2), litlSf [0~]D +38.2 (c 1.36 CH2C12), lit15b [e~]D 37.1 (c 1.51, CH2C12). IH NMR
~i (CDCI3, 500 MHz): 5.46 (IH, td, H-4", J4,, 3,,=15 Hz, J4,,,5,,=6.5 Hz), 5.33 (1H, m, H-3"), 4.25
(IH, dd, H-5, J5,4=4.6 Hz, J5,1,,=6.3 Hz), 3.94 (1H, d, H-4, J4.5=4.6 Hz), 3.79 (3H, s, OCH3), 2.89
(3H, s, NCH3), 2.18 (1H, m, H-2"a), 1.97-1.80 (2H, m, H-2"b, 1"), 1.64 (3H, d, H-5", J5,, 4,,=6.5
Hz), 0.92 (3H, d, CH3, JCH3, HI ''=6.3 Hz). 13C NMR (CDCI3) ~i: 170.2 (C-I'), 157.2 (C-2), 128.0
(C-4"), 127.2 (C-3"), 79.2 (C-5), 61.6 (C-4), 52.8 (OCH3), 37.5 (C-I"), 34.2 (C-2"), 30.0 (NCH3),
17.9 (CH3), 13.7 (C-5"). Anal. calcd for CI2HI9NO4: C, 59.73; H, 7.94; N, 5.80. Found: C, 59.75;
H, 7.96; N, 5.72.
(4S•5R)-4-Meth•x•.
•carb•nyl-2-N-methyl-5-[( •'•R•y•
Z)- •''-methy•-pent- y'-enyl]-2•2-dimethy•-2-
oxazolidinone Z-14
The N-methylation of the oxazolidinone Z-13 (83 mg), 0.37 mmoi) with methyl iodide (182 IlL,
2.92 mmol) and silver oxide (339 mg, 1.46 mmol) in dimethylformamide (2.5 mL) under the above
experimental conditions furnished after flash chromatography (cyclohexane/EtOAc 6/4 Rf 0.3) 44 mg
(50%) of Z-14. [O~]D +45 (c 1.05, CH2CI2). IH NMR (CDC13) ~5:5.52 (1H, m, H-4"), 5.30 (1H, m,
H-3"), 4.25 (1H, dd, H-5, J5,4=4.8 Hz, J5,1,,=6.4 Hz), 3.96 (1H, d, H-4, J4,5=4.8 Hz), 3.78 (3H, s,
OCH3), 2.88 (3H, s, NCH3), 2.27-2.10 (1H, m, H-2"a), 2.08-1.74 (2H, m, H-2"b, 1"), 1.57 (3H, dd,

1658
A. Tucn et al.
H-5", J5,, 4,,=6.8 Hz, J5. .,3. . .0.8 Hz), 0.92 (3H, d, JCH3, H1,,=6.8 Hz). 13C NMR (CDCl3) 6:170.2
(C-I'), 157.2 (C-2), 126.6, 126.5 (C-3",4"), 79.5 (C-5), 61.9 (C-4), 52.9 (OCH3), 37.8 (C-I"), 30.1
(NCH3), 28.3 (C-2"), 14.0 (CH3), 12.9 (C-5"). MS (EI, %) 241(20), 182(100), 138(40), 128(90),
100(40), 84(20); HRMS for C12HI9NO4: (M+) calcd 241.1314, found 241.1314.
References
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An unusual amino acid component of cyclosporin
1659
24. For analogous reactions on achiral 0(, 13-ethylenic aldehydes, see: Clive, D.L.J.; Farina, V.; Beaulieu,
P.L.J. Org. Chem. 1982, 47, 2572-2582, and references cited therein.
25. Nicolaou, K.C.; Bunnage, M.E.; Koide, K. J. Am. Chem. Soc. 1994, 116, 8402-8403.
26. In IH NMR (250 MHz), only the coupling constants 3JH.3,H_4=9.3 and 3JH-4,H-5=3.4 Hz
for the azepane 8a have been measured. These values, which suggest a trans relationship
between H3-H4,and a cis one between H4-H5, are in good agreement with those based on
molecular dynamics simulation using Insight II software (calculated: JH_3,H_4=7.7-9.8 and 7.9-9.9,
respectively for 8a and 8b; JH.4,H_5=l.9-3.8 and JH.4,H_5=9.5-I0.3, respectively for 8a and 8b).
IH NMR 2D NOESY diagram of 8a: cross signals of CH3 with H-3, CH3 with H-4, CH3 with
H-7a, CH3 with H-6a; H-6b with H-4, H-6b with H-5, H-6b with H-6a; H-2a with H-2b, H-2a
with H-3; H-4 with H-5.2D NOESY diagram of 8b: cross signals of CH3 with H-4; H-2a with
H-3, H-2a with H-2b; H-2a with H-7a; H-7a with H-7b, H-7a with H-3.
27. Okazoe, T.; Takai, K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109, 951-953.
28. This method constitutes an alternative to the reduction of a propargylic derivative by the modified
Corey-Fuchs procedure recently reported, see: D'Aniello, F.; Falorni, M.; Mann, A.; Taddei, M.
Tetrahedron: Asymmetry. 1996, 7, 1217-1226.
29. Melon, D.; Gravier-Pelletier, C.; Le Merrer, Y.; Depezay, J.-C. Bull. Soc. Chim. Fr. 1992, 129,
585-593, and references cited therein.
30. Olsen, R.K.J. Org. Chem. 1970, 35, 1912-1915.
31. The numbering system used in this paper corresponds to the current CA index names for
substructure 1. For details, see: Chemical Abstracts Service Index Guide, American Chemical
Society:
1"
C
1'
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(Received in UK 19 March 1997)