A novel asymmetric synthesis of the core octadienoic acid unit of cryptophycins from (R)-2,3- O -cyclohexylideneglyceraldehyde

Article abstract of DOI:10.1055/s-0030-1260014

A facile asymmetric synthesis of the octadienoic acid unit of cryptophycins was developed starting from (R)-2,3-O-cyclohexylideneglyceraldehyde. The key steps of the synthesis are the stereocontrolled generation of the required asymmetric centers through

Full text of DOI:10.1055/s-0030-1260014

1626
PAPER
A Novel Asymmetric Synthesis of the Core Octadienoic Acid Unit of
Cryptophycins from (R)-2,3-O-Cyclohexylideneglyceraldehyde
Dibakar Goswami, Payel Sur, Angshuman Chattopadhyay, Anubha Sharma, Subrata Chattopadhyay*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Fax +91(22)25505151; E-mail: schatt@barc.gov.in
Received 4 February 2011; revised 3 March 2011
against KB cells in vitro,6a,b but has a very short half-life.
The metabolically stable synthetic analogue, cryptophy-
cin-52 (3), shows exceptional in vivo potency and tumor-
selective cytotoxicity, and is effective against drug-sensi-
Abstract: A facile asymmetric synthesis of the octadienoic acid
unit of cryptophycins was developed starting from (R)-2,3-O-cyclo-
hexylideneglyceraldehyde. The key steps of the synthesis are the
stereocontrolled generation of the required asymmetric centers
through (i) a gallium-mediated highly diastereoselective crotylation tive and drug-resistant tumor cells.6c
of the glyceraldehyde in [bmim][Br], (ii) a stereoselective allylation
Structural variation within the subset of the macrocyclic
with allyltributylstannane, and (iii) an enantioselective Grignard ad-
cryptophycins is centered on three sites: (i) the styryl res-
idue in 5–7 that is epoxidized in 1–4, (ii) the b-alanine or
a-methylated b-alanine residue as in 2 and 7, and 1, 3–6,
respectively, and (iii) the (R)-O-methyltyrosinyl residue
of 2, 4 and 6 that bears a m-chloro substituent in 1, 3, 5 and
7. Essentially, the structure of the cryptophycins can be
assembled in a convergent manner (Figure 1) from the
protected octadienoic acid (A unit), D-tyrosine ester (B
unit), the protected b-amino acid derivative (C unit) and
the hydroxy acid (D unit). Amongst these, the presence of
the epoxide unit in unit A, the methoxy and chloro substit-
uents in unit B and certain substitution patterns in unit C
contribute positively to the cytotoxic action of the crypto-
phycins.6c In view of their potent bioactivity, a large num-
ber of formal7 and total2a,8 syntheses of the cryptophycins
have been reported. Given the units B–D are easily avail-
able, particular attention has been focused on the synthe-
sis of the octadienamide fragment (A equivalent) of
dition to an a-oxygenated aldehyde.
Key words: asymmetric synthesis, chiral pool, cryptophycins, gal-
lium, crotylation, allylation
Cryptophycins (Figure 1) are potent, tumor-selective tu-
bulin-binding antimitotic agents1 with excellent activity
against multidrug-resistant (MDR) cancer cells.2 Crypto-
phycin-A (1), initially isolated from the blue-green algae
Nostoc sp. ATCC 537893a,b and later from GSV 224,3c is
an effective inhibitor of tubulin polymerization at substo-
ichiometric concentrations4 and inhibits vinblastine bind-
ing to tubulin.4,5 A structurally related compound,
arenastatin A (cryptophycin-24, 2), isolated from the
Okinawan marine sponge Dysidea arenaria6a,b and from
Nostoc sp. GSV 224,6c is a potent inhibitor of tubulin
polymerization6d and also shows excellent cytotoxicity
O
O
O
O
O
O
HN
X
O
O
O
HN
X
O
O
N
H
O
OMe
N
H
O
OMe
R1
R2
R
cryptophycin-C (5): R = Me, X = Cl
cryptophycin-D (6): R = Me, X = H
cryptophycin-29 (7): R = H, X = Cl
cryptophycin-A (1): R1 = Me, R2 = H, X = Cl
cryptophycin-24 (2): R1 = R2 = X = H
cryptophycin-52 (3): R1 = R2 = Me, X = Cl
cryptophycin-B (4): R1 = Me, R2 = X = H
O
O
H2N
X
OH
O
HO
NH2
CO2H
OH
OH
R1 R2
C unit
HO
O
OMe
D unit
A unit
B unit
Figure 1 Chemical structures of the cryptophycins and units A–D
SYNTHESIS 2011, No. 10, pp 1626–1632
x
x.
x
x
.
2
0
1
1
Advanced online publication: 20.04.2011
DOI: 10.1055/s-0030-1260014; Art ID: Z17311SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of the Cryptophycin Core
1627
desoxycryptophycins, leading to a number of interesting The initial motivation for the present work stems from our
methodologies.7a,c,9 A strategic theme common to the ma- previous observation that the stereochemistry of crotyla-
jority of the syntheses of the epoxide-containing crypto- tion of the aldehyde 8 can be tuned by changing the metal
phycins has been the introduction of the epoxide and solvent. For example, while the zinc-mediated croty-
pharmacophore in a single late-stage operation through lation of 8 in wet tetrahydrofuran proceeds with modest
the use of m-chloroperoxybenzoic acid or dimethyldiox- anti selectivity to furnish the diastereomeric alcohols 9a–
irane. The reported epoxidation methods proceed with a c in a 2.4:33.1:64.5 ratio,11a when the reaction is carried
diastereoselectivity of 2–3:1, necessitating a chromato- out using indium in water, 9b and 9c are obtained in ~1:1
graphic separation of the desired (major) b-isomer. In ratio.11b Very recently, we found that the gallium-mediat-
contrast, the more efficient protocols are based on prior ed crotylation of 8 in [bmim][Br] proceeds with excellent
introduction of the chiral diol unit at those centers.8h,9 To diastereoselectivity to furnish 9a/9b/9c in a 3:5:92 ratio
this end, we have developed a novel asymmetric synthesis and 82% overall yield.12 It is worth mentioning that earli-
of 21 (A equivalent), bearing the chiral diol unit that can er, better stereocontrol in crotylation was accomplished
be elaborated to the cryptophycins.
with reagents such as crotyltrifluorosilane13a,b and
crotyltrifluoroborates13c that need to be synthesized sepa-
rately. In contrast, our approach,12 using inexpensive and
commercially available reagents such as crotyl bromide,
[bmim][Br] and gallium, and the widely used chiral tem-
plate 8, provides a simple and convenient strategy for
asymmetric crotylation.
Earlier, we have found that the homoallylic alcohols 9a–c,
obtained by crotylation of 2,3-O-cyclohexylideneglycer-
aldehyde (8) (Scheme 1) are versatile intermediates for
the syntheses of a variety of bioactive compounds.10 It
was envisaged that the alcohol stereomers 9a–c are func-
tionally sufficiently enriched and well-suited for elabora-
tion to the target structural motif of the A unit of the For the synthesis of the cryptophycin segment
cryptophycins. Further, following this strategy, it would (Scheme 1), compound 9c was converted into the silyl de-
be possible to introduce the required diol moiety in an rivative 10 by reaction with tert-butyldiphenylsilyl chlo-
enantioselective fashion, which would eventually produce ride in the presence of imidazole as the base. This, on
the epoxide-containing cryptophycins.
reductive ozonolysis, gave the aldehyde 11.
R1
R1
R1
O
R1
R1
O
R1
O
R1
R1
O
i
+
O
O
+
O
O
CHO
82%
OH
9b
OH
9c
OH
9a
8
R1–R1 = (CH2)5
R1
R1
R1
O
R1
O
R1
O
R1
iv
ii
v
X
O
O
9c
O
76%
93%
90%
OTBDPS
OR2 OH
OR2 OBz
12 R2 = TBDPS
10 X = CH2
11 X = O
13 R2 = TBDPS
iii, 81%
R1
O
R1
R1
R1
R1
O
R1
O
ii
vii,viii
82%
vi
O
O
O
94%
OR2 OBz
16 R2 = TBDPS
79%
OH OBz
OH OBz
14
15
OH
OH
OHC
x
xi
HO
ix
Ph
84%
OR2 OBz
19 R2 = TBDPS
93%
OR2 OBz
OR2 OBz
91%
18 R2 = TBDPS
17 R2 = TBDPS
O
O
xiii
72%
vi,xii
68%
Ph
Ph
O
OBz
O
OH
20
21
Scheme 1 Reagents and conditions: (i) MeCH=CHCH2Br, Ga, [bmim][Br], 25 °C, 4 h; (ii) TBDPSCl, imidazole, CH2Cl2, 25 °C, 12 h; (iii)
O3, CH2Cl2, –78 °C, 1 h; Ph3P, r.t., 16 h; (iv) allyltributylstannane, InCl3, (S)-BINOL, CH2Cl2, r.t., 36 h; (v) BzCN, Et3N, CH2Cl2, 0 °C to r.t.,
18 h; (vi) TBAF, THF, 0 °C, 3 h; (vii) PCC, NaOAc, CH2Cl2, 0 °C, 3 h; (viii) K-Selectride®, THF, –78 °C, 3 h; (ix) TFA, H2O, 0 °C, 3 h;
(x) NaIO4, MeCN, H2O, r.t., 2 h; (xi) PhMgBr, THF, –30 °C, 3 h; (xii) 2,2-dimethoxypropane, PPTS, r.t., 1 h; (xiii) K2CO3, MeOH, r.t., 3 h.
Synthesis 2011, No. 10, 1626–1632 © Thieme Stuttgart · New York

1628
D. Goswami et al.
PAPER
R1
R1
R1
R1
O
R1
O
R1
O
ii
O
i
O
O
O
O
OR2 OH
OH OH
12 R1–R1 = (CH2)5
12a
12b
R2 = TBDPS
R1
R1
R1
O
R1
O
R1
O
R1
iii
ii
O
O
O
O
O
OH OH
OH OBz
15
15a
15b
Scheme 2 Reagents and conditions: (i) TBAF, THF, 0 °C, 2 h; (ii) 2,2-dimethoxypropane, PPTS, r.t., 1 h; (iii) K2CO3, MeOH, 0 °C, 2 h.
It was envisaged that a substrate-controlled Barbier-type to furnish the target cryptophycin A unit 19 almost exclu-
allylation of the aldehyde 11 might provide an easy and sively. For further confirmation of its structure, com-
economic route to the desired syn-alcohol 12. For this pur- pound 19 was converted into the known compound 21,
pose, we attempted the reaction between 11 and allyl bro- that has been conceived as an advanced synthon for cryp-
mide using different metal–solvent combinations (Zn, tophycin A.9 Thus, compound 19 was desilylated and the
THF, sat. aq NH4Cl; In, H2O; In, [bmim][Br]; Ga, resultant product was converted into the acetal 20 by acid-
[bmim][Br]); however, the homoallylic alcohol 12 was catalyzed condensation with 2,2-dimethoxypropane. Sub-
obtained as a nonseparable diastereomeric mixture under sequent debenzoylation of 20 finally afforded the target
all reactions conditions. Hence, the allylation of 11 was synthon 21, whose spectroscopic and optical data were in
carried out14 with allyltributylstannane in the presence of accordance with the reported values.9
(S)-BINOL to obtain 12 with excellent (>30:1, syn/anti)
diastereoselectivity. When the reaction was carried out
with (R)-BINOL as the chiral auxiliary, the 3,5-anti-ste-
In conclusion, an efficient asymmetric synthesis of the oc-
tadienoic acid unit (A unit) of cryptophycins from the eas-
ily available aldehyde 8 has been demonstrated. Amongst
reomer of 12 was obtained with >25:1 diastereoselectivi-
the existing syntheses of the A unit, the most recent route9
ty. This suggested that the stereochemistry of the reaction
is by far the best in terms of brevity (7/8 steps) and overall
was dictated exclusively by that present in the reagent,
yield (~14%); however, it involves several reagents which
without a significant contribution from the substrate
need to be prepared separately and/or are suitable for syn-
chirality.
thesis on a very small scale. The formulation of simple
The 3,5-syn-alcohol 12 could be easily isolated by normal and efficient asymmetric syntheses of bioactive target
column chromatography. To confirm the 3,5-syn stereo- compounds remains one of the challenging goals in organ-
chemistry, 12 was converted into the acetonide derivative ic chemistry despite recent progresses.16 Compared to the
12b (Scheme 2). Thus, compound 12 was desilylated to previous syntheses, all the steps in our synthesis can be
the diol 12a and subsequently converted into the cyclic carried out conveniently on a multigram scale. Also, de-
acetal 12b by reaction with 2,2-dimethoxypropane in the spite requiring more steps, our synthesis provided the tar-
presence of pyridinium p-toluenesulfonate. The 3,5-syn get compound in acceptable overall yield (18%). The
stereochemistry was confirmed from the 13C NMR reso- present synthetic route is also amenable for the synthesis
nances.15
of other members of the cryptophycin family.
For the synthesis of the target compound (Scheme 1), the
carbinol 12 was benzoylated to furnish compound 13,
which on desilylation gave the alcohol 14. This was sub-
sequently converted into the 3,5-anti-diol derivative 15 by
oxidation of its carbinol function with pyridinium chloro-
chromate followed by reduction with K-Selectride®. As
was done for compound 12, the relative 3,5-anti stereo-
chemistry of 15 was confirmed by analyzing the 13C NMR
All chemicals (Fluka and Lancaster) were used as received. All sol-
vents were dried following standard procedures. Other reagents
were of AR grade. Unless otherwise mentioned, the organic extracts
were dried over anhyd Na2SO4. IR spectra as thin films were
1
scanned with a Jasco model A-202 FT-IR spectrophotometer. H
NMR (200 MHz) and 13C NMR (50 MHz) spectra were recorded
with a Bruker AC-200 spectrometer using CDCl3 as the solvent.
The optical rotations were recorded with a Jasco DIP-360 digital
resonances of the cyclic acetal 15b (Scheme 2). Next, the polarimeter.
alcohol 15 was silylated with tert-butyldiphenylsilyl
(3S,4S,5R)-4-tert-Butyldiphenylsilyloxy-5,6-cyclohexylidene-
dioxy-3-methylhex-1-ene (10)
chloride in the presence of imidazole to obtain compound
16, which on deketalization with aqueous trifluoroacetic
acid gave the diol 17 uneventfully (Scheme 1). Cleavage
of the a-glycol of 17 with sodium periodate furnished the
aldehyde 18. Its reaction with phenylmagnesium bromide
proceeded with excellent diastereoselectivity (dr >98:2)
To a soln of 9c (1.44 g, 6.37 mmol) and imidazole (0.828 g, 12.18
mmol) in CH2Cl2 (30 mL) was added TBDPSCl (2.51 g, 9.15
mmol), and the mixture was stirred at 25 °C for 12 h. After comple-
tion of the reaction (cf. TLC), the mixture was poured into H2O (20
mL) and extracted with CHCl3 (3 × 15 mL). The organic extract
Synthesis 2011, No. 10, 1626–1632 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of the Cryptophycin Core
1629
was washed with H2O (2 × 5 mL) and brine (1 × 5 mL), dried and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, EtOAc–hexane, 2:98) to give
pure 10.
13C NMR (50 MHz, CDCl3): d = 11.1, 19.4, 23.9, 25.0, 27.1, 35.0,
35.7, 39.6, 43.6, 68.5, 72.8, 74.2, 74.4, 110.1, 116.7, 127.6, 129.8,
129.9, 133.4, 133.6, 135.4, 136.1.
Anal. Calcd for C31H44O4Si: C, 73.18; H, 8.72. Found: C, 72.95; H,
8.78.
Yield: 2.75 g (93%); colorless liquid; [a]D23 +31.8 (c 2.31, CHCl3).
IR (film): 1586, 998, 909 cm–1.
(2R,3S,4S,5S)-1,2-Cyclohexylidenedioxy-4-methyloct-7-ene-
3,5-diol (12a)
1H NMR (200 MHz, CDCl3): d = 0.93 (d, J = 7.0 Hz, 3 H), 1.05 (s,
9 H), 1.23–1.51 (m, 10 H), 2.28–2.37 (m, 1 H), 3.70–3.86 (m, 3 H),
4.01–4.10 (m, 1 H), 4.96–5.01 (m, 2 H), 5.81–5.98 (m, 1 H), 7.22–
7.26 (m, 6 H), 7.68–7.77 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 14.2, 19.6, 23.9, 24.0, 25.3, 26.9,
27.2, 34.7, 36.2, 40.9, 66.6, 76.1, 77.8, 108.9, 114.7, 127.5, 127.6,
129.7, 129.8, 133.8, 133.9, 135.6, 136.2, 140.4.
To a cooled (0 °C) and stirred soln of 12 (0.163 g, 0.32 mmol) in
THF (10 mL) was added 1 M TBAF in THF (0.56 mL, 0.56 mmol),
and the mixture was stirred for ~2 h (cf. TLC). It was poured into
excess H2O, and this mixture was extracted with EtOAc (3 × 5 mL).
The combined organic extract was washed with H2O (1 × 5 mL) and
brine (1 × 5 mL), and dried. Removal of the solvent under reduced
pressure followed by column chromatography of the residue (silica
gel, 0–10% EtOAc–hexane) furnished pure 12a.
Anal. Calcd for C29H40O3Si: C, 74.95; H, 8.68. Found: C, 75.10; H,
8.56.
Yield: 0.068 g (78%); colorless liquid; [a]D22 +15.2 (c 1.40, CHCl3).
IR (film): 3437, 2933, 2858 cm–1.
(2R,3S,4R)-3-tert-Butyldiphenylsilyloxy-4,5-cyclohexylidene-
dioxy-2-methylpentanal (11)
1H NMR (200 MHz, CDCl3): d = 0.88 (d, J = 6.8 Hz, 3 H), 1.28–
1.61 (m, 10 H), 2.09–2.21 (m, 2 H), 2.31–2.50 (m, 1 H), 3.09 (br s,
2 H), 3.71–4.03 (m, 4 H), 4.18–4.25 (m, 1 H), 5.09–5.16 (m, 2 H),
5.72–6.03 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 12.6, 23.7, 23.9, 25.1, 34.8, 36.0,
38.7, 40.5, 64.3, 74.1, 74.5, 76.4, 109.6, 117.7, 134.9.
Ozone was bubbled through a cooled (–78 °C) soln of 10 (2.55 g,
5.49 mmol) in CH2Cl2 (20 mL) until the solution turned blue. After
1 h, the excess O3 was removed by purging with N2 (gas), and the
mixture was treated with Ph3P (6.0 g, 22.89 mmol) and stirred at r.t.
for 16 h. Most of the solvent was removed under reduced pressure,
and the residue was dissolved in hexane (30 mL) and chromato-
graphed (silica gel, 0–10% EtOAc–hexane) to furnish pure 11.
Anal. Calcd for C15H26O4: C, 66.64; H, 9.69. Found: C, 66.45; H,
9.75.
Yield: 2.08 g (81%); colorless liquid; [a]D22 +8.2 (c 1.00, CHCl3).
IR (film): 1726 cm–1.
(4S,5S,6S,7R)-7,8-Cyclohexylidenedioxy-4,6-isopropylidene-
dioxy-5-methyloct-1-ene (12b)
1H NMR (200 MHz, CDCl3): d = 1.01 (s, 9 H), 1.16–1.28 (m con-
taining a d at d 1.26, J = 7.0 Hz, 5 H), 1.41–1.48 (m, 8 H), 2.68–2.71
(m, 1 H), 3.42–3.48 (m, 1 H), 3.74–3.81 (m, 1 H), 4.12–4.22 (m, 2
H), 7.32–7.42 (m, 6 H), 7.56–7.71 (m, 4 H), 9.55 (d, J = 1.2 Hz, 1
H).
13C NMR (50 MHz, CDCl3): d = 7.4, 19.5, 23.8, 23.9, 25.1, 26.9,
34.6, 36.2, 49.9, 67.6, 73.9, 76.1, 109.6, 127.6, 127.9, 129.9, 130.2,
132.2, 133.4, 135.9, 136.2, 204.8.
A mixture of diol 12a (0.050 g, 0.185 mmol), 2,2-dimethoxypro-
pane (1 mL) and PPTS (cat.) was stirred for 1 h. Then, the mixture
was treated with 10% aq NaHCO3 and extracted with Et2O (10 mL).
The ether layer was washed with H2O (1 × 2 mL) and brine (1 × 2
mL), dried and concentrated under reduced pressure to give a resi-
due which was purified by column chromatography (silica gel, 0–
10% EtOAc–hexane) to afford 12b.
Yield: 0.048 g (84%); colorless liquid; [a]D22 +23.4 (c 1.20, CHCl3).
IR (film): 2935, 1107 cm–1.
Anal. Calcd for C28H38O4Si: C, 72.06; H, 8.21. Found: C, 71.85; H,
8.45.
1H NMR (200 MHz, CDCl3): d = 0.95 (d, J = 6.6 Hz, 3 H), 1.24–
1.42 (m overlapped with two s, 8 H), 1.55–1.59 (m, 8 H), 2.10–2.28
(m, 2 H), 2.32–2.49 (m, 1 H), 3.41–3.59 (m, 2 H), 3.85–3.90 (m, 1
H), 3.99–4.04 (m, 2 H), 5.01–5.09 (m, 2 H), 5.78–6.05 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 12.2, 19.6, 23.9, 25.2, 29.8, 35.3,
36.0, 37.1, 37.3, 66.8, 73.8, 75.0, 78.2, 97.7, 109.9, 116.4, 134.8.
(4S,5S,6S,7R)-6-tert-Butyldiphenylsilyloxy-7,8-cyclohexy-
lidenedioxy-5-methyloct-1-en-4-ol (12)
To a soln of azeotropically dried (with anhyd THF, 3 × 3 mL) InCl3
(142 mg, 0.645 mmol) in CH2Cl2 (6.5 mL) was added (S)-BINOL
(205 mg, 0.735 mmol) under argon. The mixture was stirred for 2 h,
then allyltributylstannane (0.4 mL, 1.3 mmol) was added and the re-
sulting mixture was stirred for 10 min, which was followed by the
addition of H2O (0.09 mL, 4.8 mmol) to afford a white suspension.
This mixture was further treated with allyltributylstannane (0.950
mL, 3.0 mmol), stirred for 10 min and then 11 (1.0 g, 2.15 mmol) in
CH2Cl2 (10 mL) was added. After the mixture was stirred at r.t. for
36 h, sat. aq NaHCO3 (10 mL) was added. The organic layer was
separated, the aqueous layer was extracted with CHCl3 (2 × 10 mL),
and the combined organic extracts were washed with brine, dried
and concentrated under reduced pressure. The residue was purified
by column chromatography (silica gel, 0–15% EtOAc–hexane) to
furnish pure 12.
Yield: 0.830 g (76%); colorless liquid; [a]D22 +20.1 (c 1.20, CHCl3).
IR (film): 3443 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.06 (overlapping s and d, J = 7.0
Hz, 12 H), 1.27–1.54 (m, 10 H), 1.77–1.82 (m, 1 H), 1.88–2.04 (m,
2 H), 2.75 (br s, 1 H), 3.55–3.63 (m, 2 H), 4.02–4.17 (m, 3 H), 4.92–
4.99 (m, 2 H), 5.61–5.75 (m, 1 H), 7.34–7.44 (m, 6 H), 7.64–7.70
(m, 4 H).
Anal. Calcd for C18H30O4: C, 69.64; H, 9.74. Found: C, 69.75; H,
9.80.
(4S,5S,6S,7R)-4-Benzoyloxy-6-tert-butyldiphenylsilyloxy-7,8-
cyclohexylidenedioxy-5-methyloct-1-ene (13)
To a cooled (0 °C) and stirred soln of the alcohol 12 (0.800 g, 1.58
mmol) and Et3N (0.350 mL, 2.34 mmol) in CH2Cl2 (15 mL) was
added BzCN (0.484 mL, 4.08 mmol). After the mixture was stirred
at r.t. for 18 h, it was poured into H2O (15 mL); the organic layer
was separated and the aqueous layer was extracted with CHCl3
(2 × 5 mL). The combined organic extracts were washed with H2O
(1 × 5 mL) and brine (1 × 5 mL), and dried. Removal of the solvent
under reduced pressure followed by column chromatography of the
residue (silica gel, 0–10% EtOAc–hexane) furnished pure 13 as a
mixture of rotamers.
22
Yield: 0.858 g (90%); light yellow liquid; [a]D +13.5 (c 2.52,
CHCl3).
IR (film): 2935, 2857, 1638 cm–1.
Synthesis 2011, No. 10, 1626–1632 © Thieme Stuttgart · New York

1630
D. Goswami et al.
PAPER
1H NMR (200 MHz, CDCl3): d = 1.16 (overlapping s and d, J = 7.0
Hz, 12 H), 1.23–1.54 (m, 10 H), 1.92–2.10 (m, 1 H), 2.23–2.31 (m,
2 H), 3.75–3.86 (m, 2 H), 3.89–3.99 (m, 1 H), 4.13–4.21 (m, 1 H),
4.87–5.01 (m, 2 H), 5.45–5.52 (m, 1 H), 5.56–5.77 (m, 1 H), 7.29–
7.45 (m, 9 H), 7.66–7.92 (m, 5 H), 7.98–8.05 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 10.6, 11.0, 19.5, 23.7, 23.8, 25.1,
27.1, 34.7, 34.9, 35.7, 36.1, 36.8, 40.1, 40.5, 64.0, 67.8, 73.5, 73.8,
75.1, 75.5, 76.5, 109.4, 109.6, 116.9, 117.0, 127.4, 127.5, 128.3,
129.1, 129.4, 129.6, 129.7, 129.8, 130.2, 132.1, 132.9, 133.8, 133.9,
134.1, 135.8, 136.0, 136.1, 165.4, 165.5.
13C NMR (50 MHz, CDCl3): d = 15.0, 23.7, 23.8, 25.0, 34.7, 36.1,
40.6, 64.4, 73.8, 76.2, 79.1, 109.1, 114.9, 129.4, 130.3, 133.2,
136.7, 140.4, 167.7.
Anal. Calcd for C22H30O5: C, 70.56; H, 8.07. Found: C, 70.71; H,
8.15.
(2R,3R,4S,5S)-1,2-Cyclohexylidenedioxy-4-methyloct-7-ene-
3,5-diol (15a)
A mixture of 15 (0.100 g, 0.267 mmol) and anhyd K2CO3 (0.062 g,
0.454 mmol) in MeOH (10 mL) was stirred at 0 °C. After consump-
tion of the starting material (cf. TLC, ~2 h), the mixture was con-
centrated under reduced pressure, the residue was taken up in Et2O
(10 mL), and the organic extract was washed with H2O (2 × 5 mL)
and brine (1 × 5 mL), and dried. Removal of the solvent under re-
duced pressure followed by preparative TLC of the residue (silica
gel, 0–10% EtOAc–hexane) furnished pure 15a.
Yield: 0.054 g (75%); colorless liquid; [a]D22 +7.3 (c 2.3, CHCl3).
IR (film): 3438, 2933, 2857 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.03 (d, J = 6.0 Hz, 3 H), 1.29–
1.63 (m, 10 H), 2.34–2.37 (m, 1 H), 2.39–2.42 (m, 2 H), 3.02 (br s,
2 H), 3.37–3.42 (m, 1 H), 3.49–3.65 (m, 1 H), 3.79–3.83 (m, 1 H),
3.91–3.98 (m, 1 H), 4.05–4.12 (m, 1 H), 4.99–5.07 (m, 2 H), 5.70–
5.84 (m, 1 H).
Anal. Calcd for C38H48O5Si: C, 74.47; H, 7.89. Found: C, 74.28; H,
7.78.
(2R,3S,4S,5S)-5-Benzoyloxy-1,2-cyclohexylidenedioxy-4-meth-
yloct-7-en-3-ol (14)
Desilylation of 13 (0.800 g, 1.33 mmol) with 1 M TBAF in THF
(2.25 mL, 2.25 mmol) in THF (20 mL) at 0 °C for 3 h, followed by
workup of the reaction mixture and purification of the residue by
column chromatography (silica gel, 0–10% EtOAc–hexane) fur-
nished pure 14.
Yield: 0.390 g (79%); colorless liquid; [a]D22 +18.7 (c 1.60, CHCl3).
IR (film): 3437, 1720 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.06 (d, J = 7.4 Hz, 3 H), 1.20–
1.36 (m, 2 H), 1.48–1.57 (m, 8 H), 2.01–2.13 (m, 1 H), 2.35–2.52
(m, 3 H), 3.72–3.89 (m, 3 H), 4.03–4.21 (m, 1 H), 4.97–5.13 (m, 2
H), 5.43–5.50 (m, 1 H), 5.72–5.93 (m, 1 H), 7.35–7.51 (m, 3 H),
7.92–8.08 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 11.4, 23.7, 23.9, 25.1, 34.4, 34.9,
36.0, 38.9, 64.1, 71.7, 74.7, 109.4, 117.5, 128.3, 129.5, 130.5,
132.8, 134.2, 165.9.
13C NMR (50 MHz, CDCl3): d = 11.4, 23.8, 23.9, 25.0, 35.2, 36.1,
38.0, 40.7, 65.9, 72.3, 76.9, 77.8, 110.0, 115.8, 139.4.
Anal. Calcd for C15H26O4: C, 66.64; H, 9.69. Found: C, 66.42; H,
9.48.
(4S,5S,6R,7R)-7,8-Cyclohexylidenedioxy-4,6-isopropylidene-
dioxy-5-methyloct-1-ene (15b)
As described for 12a, reaction of diol 15a (0.030 g, 0.111 mmol)
with 2,2-dimethoxypropane (1 mL) in the presence of PPTS afford-
ed 15b after workup of the reaction mixture and column chromatog-
raphy of the residue (silica gel, 0–10% EtOAc–hexane).
Anal. Calcd for C22H30O5: C, 70.56; H, 8.07. Found: C, 70.35; H,
7.96.
(2R,3R,4S,5S)-5-Benzoyloxy-1,2-cyclohexylidenedioxy-4-meth-
yloct-7-en-3-ol (15)
Yield: 0.029 g (83%); colorless liquid; [a]D22 +7.3 (c 2.32, CHCl3).
To a cooled (0 °C) and stirred suspension of PCC (0.334 g, 1.52
mmol) and NaOAc (10 mol%) in CH2Cl2 (20 mL) was added the al-
cohol 14 (0.350 g, 0.95 mmol) in one portion. The reaction mixture
was stirred for 3 h, then diluted with Et2O (20 mL). The supernatant
was passed through a pad of silica gel (2¢¢ × 1¢¢), which was washed
with Et2O (15 mL). Removal of the solvent under reduced pressure
followed by column chromatography of the residue (silica gel, 0–
10% EtOAc–hexane) furnished the corresponding ketone.
IR (film): 2935, 2858, 1104 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.06 (d, J = 6.6 Hz, 3 H), 1.30 (s,
6 H), 1.33–1.59 (m, 10 H), 1.88–2.09 (m, 2 H), 2.21–2.39 (m, 1 H),
3.13–3.19 (m, 1 H), 3.56–3.68 (m, 1 H), 3.74–3.78 (m, 1 H), 3.95–
4.05 (m, 2 H), 4.97–5.09 (m, 2 H), 5.71–5.95 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 13.1, 23.5, 23.9, 24.0, 25.2, 25.3,
34.7, 34.8, 36.7, 42.0, 67.8, 70.9, 73.5, 77.9, 100.3, 109.6, 114.4,
140.8.
In view of its instability, the ketone was directly used for the next
step. Thus, 1 M K-Selectride® in THF (1.30 mL, 1.30 mmol) was
injected into a cooled (–78 °C) and stirred solution of the above ke-
tone (0.290 g, 0.78 mmol) in THF (15 mL). The mixture was stirred
at that same temperature until completion of the reaction (cf. TLC,
~3 h), then the excess hydride was decomposed with MeOH, and
the supernatant was decanted and concentrated under reduced pres-
sure. The residue was taken up in Et2O (3 × 15 mL), and the organic
extract was washed with H2O (2 × 10 mL) and brine (1 × 5 mL), and
dried. Removal of the solvent under reduced pressure followed by
column chromatography of the residue (silica gel, 0–10% EtOAc–
hexane) furnished pure 15.
Anal. Calcd for C18H30O4: C, 69.64; H, 9.74. Found: C, 69.72; H,
9.56.
(4S,5S,6R,7R)-4-Benzoyloxy-6-tert-butyldiphenylsilyloxy-7,8-
cyclohexylidenedioxy-5-methyloct-1-ene (16)
Reaction of 15 (0.120 g, 0.321 mmol) with TBDPSCl (0.149 g,
0.543 mmol) in the presence of imidazole (0.044 g, 0.641 mmol) in
CH2Cl2 (5 mL), and subsequent isolation, afforded a rotameric mix-
ture of 16 after purification by column chromatography (silica gel,
0–10% Et2O–hexane).
22
Yield: 0.189 g (94%); light yellow liquid; [a]D +10.9 (c 1.41,
CHCl3).
IR (film): 1741 cm–1.
Yield: 0.291 g (82%); colorless liquid; [a]D22 +38.8 (c 1.06, CHCl3).
IR (film): 3477, 1724 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.03 (d, J = 7.2 Hz, 3 H), 1.32–
1.36 (m, 2 H), 1.37–1.57 (m, 8 H), 2.09–2.21 (m, 1 H), 2.26–2.34
(m, 2 H), 3.50–3.54 (m, 1 H), 3.87–3.94 (m, 2 H), 4.13–4.18 (m, 1
H), 4.34–4.45 (m, 1 H), 5.03–5.12 (m, 2 H), 5.25–5.32 (m, 1 H),
5.78–5.93 (m, 1 H), 7.39–7.53 (m, 3 H), 7.99–8.06 (m, 2 H).
1H NMR (200 MHz, CDCl3): d = 1.06–1.16 (merged s and d,
J = 6.8 Hz, 12 H), 1.27–1.39 (m, 6 H), 1.44–1.56 (m, 4 H), 1.88–
2.08 (m, 1 H), 2.18–2.32 (m, 2 H), 3.76–3.86 (m, 1 H), 3.89–3.99
(m, 1 H), 4.12–4.30 (m, 2 H), 4.79–4.99 (m, 2 H), 5.22–5.28 and
5.44–5.52 (two m, 1 H), 5.57–5.75 (m, 1 H), 7.25–7.48 (m, 9 H),
7.62–7.77 (m, 5 H), 7.89–8.05 (m, 1 H).
Synthesis 2011, No. 10, 1626–1632 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of the Cryptophycin Core
1631
13C NMR (50 MHz, CDCl3): d = 10.6, 11.2, 19.5, 23.7, 23.8, 25.1,
27.1, 34.7, 34.9, 35.7, 36.1, 36.8, 40.1, 40.5, 64.0, 67.8, 73.5, 73.9,
75.1, 75.3, 75.5, 77.8, 109.4, 109.6, 117.0, 118.0, 127.4, 127.5,
128.3, 129.1, 129.4, 129.6, 129.7, 129.8, 130.2, 132.1, 132.9, 133.8,
133.9, 134.1, 135.8, 136.0, 136.1, 165.4, 165.5.
and column chromatography of the residue (silica gel, 0–15%
EtOAc–hexane) afforded pure alcohol 19.
Yield: 0.086 g (84%); white solid; [a]D22 –5.2 (c 1.21, CHCl3).
IR (film): 3478, 1721 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.05 (s, 9 H), 1.12 (d, J = 7.4 Hz,
3 H), 1.86–2.12 (m, 3 H), 2.20–2.49 (m, 1 H), 4.18 (t, J = 3.4 Hz, 1
H), 4.75–4.84 (m, 2 H), 4.88–4.97 (m, 2 H), 5.37–5.54 (m, 1 H),
7.03–7.17 (m, 7 H), 7.25–7.43 (m, 9 H), 7.55–7.65 (m, 2 H), 7.74–
7.78 (m, 2 H).
Anal. Calcd for C38H48O5Si: C, 74.47; H, 7.89. Found: C, 74.55; H,
7.76.
(2R,3R,4S,5S)-5-Benzoyloxy-3-tert-butyldiphenylsilyloxy-
4-methyloct-7-ene-1,2-diol (17)
13C NMR (50 MHz, CDCl3): d = 10.6, 19.5, 27.1, 36.0, 38.9, 65.2,
74.2, 74.9, 117.3, 127.1, 128.3, 128.4, 128.6, 128.7, 129.7, 130.1,
132.9, 137.6, 139.9, 166.3.
A mixture of 16 (0.150 g, 0.244 mmol) and 80% aq TFA (10 mL)
was stirred at 0 °C for 3 h. The mixture was diluted with H2O (15
mL) and extracted with CHCl3 (2 × 15 mL); the organic layer was
separated and the aqueous layer was extracted with CHCl3 (2 × 5
mL). The combined organic extracts were washed successively with
2% aq NaHCO3 (1 × 10 mL), H2O (2 × 10 mL) and brine (1 × 5
mL), and dried. Solvent removal under reduced pressure followed
by column chromatography of the residue (silica gel, 0–40%
EtOAc–hexane) furnished pure 17.
Anal. Calcd for C37H42O4Si: C, 76.78; H, 7.31. Found: C, 76.98; H,
7.42.
(4S,5S,6R,7R)-4-Benzoyloxy-6,7-isopropylidenedioxy-5-meth-
yl-7-phenylhept-1-ene (20)
As described for 13, treatment of 19 (0.150 g, 0.26 mmol) with 1 M
TBAF in THF (0.30 mL, 0.30 mmol) in THF (10 mL), followed by
workup of the reaction mixture and preparative TLC of the residue
(silica gel, MeOH–CHCl3, 1:19) furnished the pure desilylated
product (0.071 g, 81%). This material (0.21 mmol) on stirring with
PPTS (cat.) in 2,2-dimethoxypropane (1 mL) for 1 h, followed by
isolation of the product and preparative TLC (silica gel, EtOAc–
hexane, 1:9), afforded 20.
Yield: 0.067 g (84%); colorless oil; [a]D22 +11.2 (c 1.05, CHCl3).
IR (film): 2923, 1718 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.02 (d, J = 7.2 Hz, 3 H), 1.28 (s,
3 H), 1.35 (s, 3 H), 1.82–1.89 (m, 1 H), 2.15–2.26 (m, 2 H), 4.15
(dd, J = 8.2, 3.6 Hz, 1 H), 4.72–4.85 (m, 2 H), 4.89–4.96 (m, 2 H),
5.28–5.52 (m, 1 H), 7.28–7.48 (m, 8 H), 7.95–8.10 (m, 2 H).
Yield: 0.118 g (91%); colorless liquid; [a]D22 +4.0 (c 1.34, CHCl3).
IR (film): 3438, 1721 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.09 (s, 9 H), 1.16 (d, J = 7.2 Hz,
3 H), 1.60 (br s, 2 H), 2.12–2.28 (m, 2 H), 2.32–2.51 (m, 1 H), 3.25–
3.39 (m, 1 H), 3.54–3.75 (m, 3 H), 4.96–5.07 (m, 2 H), 5.32–5.39
(m, 1 H), 5.55–5.71 (m, 1 H), 7.12–7.41 (m, 8 H), 7.45–7.58 (m, 5
H), 7.80–7.84 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 10.2, 19.5, 27.1, 36.7, 41.9, 64.4,
72.2, 73.6, 77.8, 118.0, 127.5, 127.6, 128.3, 129.7, 133.1, 135.8,
136.0, 167.0.
Anal. Calcd for C32H40O5Si: C, 72.14; H, 7.57. Found: C, 72.33; H,
7.36.
13C NMR (50 MHz, CDCl3): d = 10.2, 26.8, 27.0, 35.8, 40.1, 72.8,
79.5, 83.2, 108.6, 116.8, 127.2, 127.8, 128.5, 128.9, 133.0, 136.5,
168.1.
(2R,3S,4S)-4-Benzoyloxy-2-tert-butyldiphenylsilyloxy-3-meth-
ylhept-6-enal (18)
To a stirred soln of diol 17 (0.100 g, 0.188 mmol) in 60% aq MeCN
(20 mL) at r.t. was added NaIO4 (0.080 g, 0.376 mmol) in portions.
The mixture was stirred for 2 h, then filtered, and the filtrate was ex-
tracted with CHCl3 (2 × 10 mL). The organic layer was washed with
H2O (2 × 10 mL) and brine (1 × 5 mL), and concentrated under re-
duced pressure to give the aldehyde 18.
Yield: 0.087 g (93%); colorless liquid; [a]D23 +9.2 (c 1.22, CHCl3).
IR (film): 2710, 1730, 1712 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.10 (overlapping s and d, J = 6.8
Hz, 12 H), 1.95–2.03 (m, 1 H), 2.21–2.29 (m, 2 H), 4.21 (dd,
J = 1.8, 2.4 Hz, 1 H), 4.87–5.02 (m, 2 H), 5.23–5.29 (m, 1 H), 5.62–
5.83 (m, 1 H), 7.15–7.47 (m, 9 H), 7.49–7.60 (m, 4 H), 7.78–7.82
(m, 2 H), 9.35 (d, J = 1.8 Hz, 1 H).
Anal. Calcd for C24H28O4: C, 75.76; H, 7.42. Found: C, 75.61; H,
7.25.
(4S,5S,6R,7R)-6,7-Isopropylidenedioxy-5-methyl-7-phenyl-
hept-1-en-4-ol (21)
Hydrolysis of 20 (0.060 g, 0.16 mmol) with K2CO3 (0.048 g, 0.35
mmol) in MeOH (5 mL), followed by the usual workup of the reac-
tion mixture and column chromatography of the residue (silica gel,
0–20% EtOAc–hexane), furnished pure 21.
Yield: 0.031 g (72%); colorless liquid; [a]D22 –3.4 (c 1.12, CHCl3)
[Lit.9 [a]D24 –3.34 (c 2.21, CHCl3)].
IR (film): 3485, 2923 cm–1.
13C NMR (50 MHz, CDCl3): d = 11.6, 19.5, 27.4, 36.7, 42.1, 74.5,
81.1, 116.9, 127.2, 127.5, 128.1, 129.2, 132.9, 136.0, 136.2, 140.8,
169.2, 203.4.
1H NMR (200 MHz, CDCl3): d = 1.05 (d, J = 7.2 Hz, 3 H), 1.58 (s,
3 H), 1.62 (s, 3 H), 1.72–1.79 (m, 1 H), 2.07 (br s, 1 H), 2.12–2.28
(m, 2 H), 3.52–3.62 (m, 1 H), 4.12 (dd, J = 9.2, 2.4 Hz, 1 H), 4.72
(d, J = 9.2 Hz, 1 H), 4.99–5.16 (m, 2 H), 5.68–5.92 (m, 1 H), 7.26–
7.42 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 10.5, 27.0, 27.2, 36.0, 39.5, 73.5,
79.9, 82.6, 108.7, 117.5, 126.8, 127.9, 128.5, 134.8, 137.5.
Anal. Calcd for C31H36O4Si: C, 74.36; H, 7.25. Found: C, 74.24; H,
7.15.
(1R,2R,3S,4S)-4-Benzoyloxy-2-tert-butyldiphenylsilyloxy-
3-methyl-1-phenylhept-6-en-1-ol (19)
Anal. Calcd for C17H24O3: C, 73.88; H, 8.75. Found: C, 73.63; H,
8.61.
To a cooled (–30 °C) and stirred soln of PhMgBr [prepared from 1-
bromobenzene (0.056 g, 0.353 mmol) and Mg turnings (0.011 g,
0.441 mmol)] in THF (10 mL) was injected aldehyde 18 (0.089 g,
0.177 mmol) in THF (10 mL). The mixture was stirred for 3 h, then
the reaction was quenched with sat. aq NH4Cl (2 mL). The organic
layer was separated and the aqueous portion was extracted with
Et2O (2 × 15 mL). The combined organic extracts were washed with
brine (1 × 5 mL) and dried. Solvent removal under reduced pressure
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Synthesis 2011, No. 10, 1626–1632 © Thieme Stuttgart · New York

1632
D. Goswami et al.
PAPER
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