Enantioselective synthesis of an analogue of nanaomycin A

Article abstract of DOI:10.1055/s-2007-983848

The enantioselective synthesis of (1R,3R)-deoxynanaomycin A (4) is reported. The key step involves introduction of the Stereocenter in (S)-homoallylic alcohol 10a using an asymmetric allylation of aldehyde 9. Lithium-halogen exchange of bromo acetate 11 triggered rapid intramolecular cyclization furnishing lactol 12 that underwent silane-mediated reduction providing (1R,3S)-naphthopyran 13. Dihydroxylation and oxidative cleavage gave aldehyde 15 that underwent two successive oxidations delivering (1R,3R)-deoxynanaomycin A (4) in high enantiopurity and an overall 7% yield over 12 steps from 1-naphthol (5). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983848

PAPER
2887
Enantioselective Synthesis of an Analogue of Nanaomycin A
E
nantioselective Synth
a
e
sis of
a
N
a
r
naomyc
g
in A
A
nalog
a
Department of Chemistry, University of Auckland, Private Bag 92019, 23 Symonds Street, Auckland, New Zealand
Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
Received 30 May 2007
thesis of nanaomycin A (1) have been reported,4 as well as
the synthesis of racemic deoxynanaomycin A as its meth-
yl ester.5,6 We herein report an enantioselective approach
to cis-deoxynanaomycin A (4). The retrosynthetic analy-
Abstract: The enantioselective synthesis of (1R,3R)-deoxynanao-
mycin A (4) is reported. The key step involves introduction of the
stereocenter in (S)-homoallylic alcohol 10a using an asymmetric al-
lylation of aldehyde 9. Lithium–halogen exchange of bromo acetate
11 triggered rapid intramolecular cyclization furnishing lactol 12 sis is based upon the use of homoallylic alcohol 10a in
that underwent silane-mediated reduction providing (1R,3S)-naph-
thopyran 13. Dihydroxylation and oxidative cleavage gave alde-
which the stereochemistry at C-3 is introduced using an
asymmetric allylation of aldehyde 9, which in turn can be
hyde 15 that underwent two successive oxidations delivering
prepared from allylbromonaphthalene 8. Lithium–halo-
(1R,3R)-deoxynanaomycin A (4) in high enantiopurity and an over-
gen exchange of 10a followed by trapping of the resulting
all 7% yield over 12 steps from 1-naphthol (5).
aryllithium with an acyl equivalent would trigger intramo-
Key words: pyranonaphthoquinone antibiotics, nanaomycin A,
lecular cyclization, furnishing (1R,3R)-deoxynanaomycin
asymmetric allylation, intramolecular cyclization
A (4) after oxidation of the C-3 side chain (Scheme 1).
OMe
O
Nanaomycin A (1), isolated by Omura and co-workers1
from the fungus Streptomyces rosa, belongs to the mono-
meric class of pyranonaphthoquinone antibiotics.2,3 It
possesses C-1–C-3 trans stereochemistry on the pyran
ring and is closely related to dihydrokalafungin (2) and
deoxyfrenolicin (3) (Figure 1). Nanaomycin A has
aroused interest due to its inhibitory activity against my-
coplasma, fungi and Gram-positive bacteria, as well as the
inhibition of the platelet-aggregation agent adenosine
diphosphate (ADP).3
Br
OH
O
CO2H
OMe
O
4
10a
OMe
OMe
Br
Br
CHO
OH
O
OH
O
OMe
9
OMe
8
2
1
4
O
3
O
CO2H
CO2H
Scheme 1 Retrosynthesis of cis-deoxynanaomycin A (4)
O
O
(1R,3S)-dihydrokalafungin (2)
(1S,3R)-nanaomycin A (1)
Initially, attention focused on the synthesis of racemic ho-
moallylic alcohol 10 in order to gauge the viability of the
proposed approach. Oxidative bromination of 1-naphthol
(5) using N-bromosuccinimide in acetic acid delivered 2-
bromo-1,4-naphthoquinone7 (6) in excellent yield. Radi-
cal allylation of 6 using a silver persulfate catalyzed oxi-
dative decarboxylation of vinylacetic acid effected
introduction of the allyl side chain at C-2 affording 2-al-
lylnaphthoquinone 78 in 67% yield. Reductive
methylation9 of 7 then provided allylbromonaphthalene
8.8,10,11 Next, ozonolysis12 of 8 in dichloromethane at
–60 °C delivered aldehyde 9 which underwent smooth
Grignard reaction with freshly prepared allylmagnesium
bromide furnishing the racemic homoallylic alcohol 10 in
90% yield (Scheme 2).
OH
O
O
O
CO2H
(1R,3S)-deoxyfrenolicin (3)
Figure 1 Pyranonaphthoquinone family representatives
Given the significant biological activity of nanaomycin A
(1) combined with our continuing interest in the synthesis
of this class of compounds, we were interested in develop-
ing a flexible enantioselective route that would prove via-
ble for producing closely related analogues of this natural
product. To date, several approaches for the racemic syn-
Having established a protocol for the synthesis of homoal-
lylic alcohol 10 in racemic form via the allylation of alde-
hyde 9, various enantioselective allylation procedures
were considered. Early efforts at conducting the asymmet-
SYNTHESIS 2007, No. 18, pp 2887–2893
Advanced online publication: 08.08.2007
DOI: 10.1055/s-2007-983848; Art ID: P06707SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7

2888
M. A. Brimble et al.
PAPER
OH
O
O
Br
Br
+
(ii)
(i)
HO2C
O
7
O
6
5
OMe
OMe
OMe
Br
Br
Br
(iv)
(iii)
OH
(v)
CHO
OMe
OMe
OMe
8
10
9
Scheme 2 Reagents and conditions: (i) NBS, AcOH, H2O, 45 °C, 1 h, 87%; (ii) AgNO3, (NH4)2S2O8, MeCN, H2O, 65 °C, 2 h, 67%; (iii)
Na2S2O4, TBAI, THF, aq KOH, Me2SO4, 4 h, 95%; (iv) O3, Sudan III, CH2Cl2, –60 °C, 15 min, 85%; (v) allylmagnesium bromide, Et2O, –
40 °C to r.t., 6 h, 90%.
ric allylation of aldehyde 9 included using allyltributyl-
OMe
OMe
B
stannane with (S)-BINOL/InCl3,13 allyltrimethylsilane
Br
Br
17
2
14
OH
with (S)-BINOL/TiF4 and allyltributylstannane with
(R)-BINOL/Ti(Oi-Pr)4.15 Disappointingly, all these meth-
ods failed to give 10a with satisfactory enantioselectivity
(Table 1). At this point, focus turned to the popular asym-
metric allylation reaction developed by Brown and co-
workers.16 B-Allyldiisopinocampheylborane (17) was
made by using freshly prepared allylmagnesium bromide
and (–)-B-diisopinocampheylmethoxyborane according
to a published protocol.16a,b Addition of aldehyde 9 to the
resulting B-allyldiisopinocampheylborane (17) in diethyl
ether at –78 °C did not furnish the expected homoallylic
alcohol 10a. This was attributed to the possible presence
of magnesium salts and/or the poor reliability of the pre-
cursor B-diisopinocampheylmethoxyborane, an observa-
tion also noted by Felpin et al.17 As a result, it was decided
to prepare the allylborane from commercially available
(–)-DIP-Chloride® [(–)-B-chlorodiisopinocampheylbo-
rane]. Thus, freshly prepared allylmagnesium bromide
was added to (–)-DIP-Chloride® at 0 °C under nitrogen
and the mixture was stirred for 1 hour at room tempera-
ture. To the magnesium salt free ethereal solution of the
resulting (+)-B-allyldiisopinocampheylborane (17) was
added aldehyde 9 at –78 °C then the mixture was stirred
for 3 hours. The (S)-homoallylic alcohol 10a was isolated
in 62% yield and its enantiomeric excess was calculated to
be 82%, as determined by chiral HPLC using a Chiralcel®
OD-H column (Scheme 3). Based on the literature proce-
dure homoallylic alcohol 10a was assigned the S configu-
ration. This conclusion was supported by adoption of the
favored transition state described by Brown and co-work-
ers,16e–g and also agreed with the assessment made for Al-
pine-Borane® reductions proceeding via a six-membered
cyclic boatlike transition state as suggested by Midland
and Zderic.18
CHO
OMe
OMe
9
(S)-10a
Scheme 3 Reagents and conditions: allylmagnesium bromide, DIP-
Chloride®, Et2O, –78 °C, 3 h, 62%, 82% ee.
sumably via internal quenching of the anion by the
adjacent acidic alcohol proton. This result is supported by
the reports of Narasimhan et al. that the lithium–halogen
exchange is in fact faster than lithium–acidic proton ex-
change in aromatic compounds.19b Because of this, it was
decided to modify the route to the desired lactol 12. In or-
der to avoid internal quenching of the aryllithium by the
adjacent hydroxy proton, it was envisaged that the alcohol
could be protected with an acetyl group. In this new ap-
proach, the aryllithium obtained from the halogen–lithium
exchange reaction would undergo intramolecular cycliza-
tion with the adjacent acetyl group delivering the desired
lactol 12.
According to this revised strategy, (S)-homoallylic acetate
11 was prepared in 90% yield from (S)-10a using acetic
anhydride in dichloromethane in the presence of a catalyt-
ic quantity of perchloric acid (Scheme 4). (S)-Homoallyl-
ic acetate 11 was treated with tert-butyllithium at –78 °C,
Table 1 Attempted Asymmetric Allylations of Aldehyde 9
Method
Yield (%) ee (%)
allyltributylstannane and (S)-BINOL/InCl3
allyltrimethylsilane and (S)-BINOL/TiF4
57
62
0
14
25a
82
allyltributylstannane and (R)-BINOL/Ti(Oi-Pr)4 54
Lithium–halogen exchange of (S)-10a followed by Wein-
reb acylation19a with N-methoxy-N-methylacetamide dis-
appointingly did not trigger intramolecular cyclization.
Instead of acylation, the C-2 position of (S)-10a under-
went protonation after lithium–halogen exchange, pre-
B-allyldiisopinocampheylborane
a (R)-Homoallylic alcohol.
62
Synthesis 2007, No. 18, 2887–2893 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of a Nanaomycin A Analogue
2889
undergoing cyclization in situ and gratifyingly affording permanganate25 and OXONE®26 oxidation procedures af-
lactol 12 as an unstable colorless oil in an excellent 97% forded the (1R,3R)-carboxylic acid 16 in a poor 18% and
yield. The lactol 12 was not fully characterized because of 45% yield, respectively. After much experimentation, a
its instability. Therefore, lactol 12 was swiftly converted solution of (1R,3R)-aldehyde 15 in tert-butyl alcohol was
into the stable (1R,3S)-naphthopyran 13 in 78% yield us- treated with sodium chlorite,27 gratifyingly giving the
ing the silane-promoted reduction reported by Kraus et (1R,3R)-carboxylic acid 16 in 68% yield. The enantiomer-
al.19c The NOESY spectrum recorded for (1R,3S)-13 con- ic excess was determined to be 82% by chiral HPLC using
firmed the cis stereochemistry between 1-H and 3-H.
a Chiralcel® AD-H column.
Having successfully constructed the pyran ring system in With the successful synthesis of (1R,3R)-carboxylic acid
naphthopyran 13, it remained to complete conversion of 16, the final oxidative demethylation step was considered.
the allyl moiety into the carboxylic acid observed in the Thus, addition of an aqueous solution of cerium(IV) am-
C-3 side chain of nanaomycin A (1). Following this pro- monium nitrate28 to a cooled solution of 16 in acetonitrile
posed strategy, use of a one-pot oxidative cleavage proce- afforded cis-(1R,3R)-deoxynanaomycin A (4) in 74%
dure reported by Pappo et al.20 disappointingly did not yield, completing an enantioselective synthesis of a close-
furnish aldehyde 15 as expected. Employing the Sharpless ly related analogue of nanaomycin A (1). The NOESY
RuCl3/NaIO4 method21 and Lemieux–Von Rudloff spectrum recorded for (1R,3R)-pyranonaphthoquinone 4
oxidation22 also met with failure, with only decomposition confirmed the cis stereochemistry between 1-H and 3-H
of 13 observed in all cases. An attempt to convert the allyl (Scheme 4).
group into an ester using the procedure of Marshall et al.23
also failed.
In summary, an efficient enantioselective synthesis of
(1R,3R)-deoxynanaomycin A (4) has been completed in
Following these disappointing results, attention turned to 12 steps starting from 1-naphthol (5) in an overall 7%
a stepwise route. In this fashion, selective dihydroxylation yield. The key step involved construction of the stereo-
of the allylic moiety in naphthopyran 13 was achieved us- center in (S)-homoallylic alcohol 10a in excellent yield
ing an osmium tetroxide catalyzed oxidation in the pres- and enantioselectivity using a Brown asymmetric allyla-
ence of N-methylmorpholine N-oxide.24 This successfully tion. Acetate 11 underwent lithium–halogen exchange
resulted in an inseparable 1:1 diastereomeric mixture of and rapid intramolecular cyclization delivering lactol 12
1,2-diols 14a and 14b that underwent smooth oxidative that underwent triethylsilane-mediated reduction giving
cleavage in the presence of sodium periodate24 furnishing (1R,3S)-naphthopyran 13. A dihydroxylation–oxidative
(1R,3R)-aldehyde 15 in an excellent 72% yield over the cleavage sequence of the allyl group in (1R,3S)-naphtho-
two steps.
pyran 13 afforded (1R,3R)-aldehyde 15 that underwent
side-chain oxidation delivering carboxylic acid 16 in high
Next, the desired transformation of aldehyde 15 into car-
boxylic acid 16 was evaluated. The use of potassium
OMe
MeO
OH
O
O
OMe
Br
Br
OH
i
O
ii
MeO
OMe
(S)-10a
OMe
(S)-11
12
MeO
MeO
MeO
1
O
3
iii
iv
O
OH
2'
v
O
OH
CHO
MeO
(1R,3S)-13
MeO
MeO
(1R,3R)-15
(1R,2'R,3R)-14a and (1R,2'S,3R)-14b
H
2
O
Me
4
1
MeO
O
H
3
HOOC
H
H
O
O
vi
vii
δ 4.85–4.94, m
CO2H
CO2H
δ 3.90–3.99, m
NOE observed
(1R,3R)-4
MeO
(1R,3R)-16
O
(1R,3R)-4
Scheme 4 Reagents and conditions: (i) Ac2O, HClO4, CH2Cl2, r.t., 2 h, 90%; (ii) t-BuLi, THF, –78 °C, 1 h, 97%; (iii) TES, TFA, CH2Cl2,
–78 °C to r.t., 2 h, 78%; (iv) OsO4, NMO, acetone, H2O, 0 °C to r.t., 24 h, 90%; (v) NaIO4, MeOH, H2O, 0 °C, 2 h, 81%; (vi) NaClO2,
NaH2PO4·2H2O, t-BuOH, cyclohexene, 68%, 82% ee; (vii) CAN, MeCN, H2O, 0 °C, 10 min, 74%.
Synthesis 2007, No. 18, 2887–2893 © Thieme Stuttgart · New York

2890
M. A. Brimble et al.
PAPER
J2¢,3¢B = 16.9 Hz, J2¢,3¢A = 9.6 Hz, J2¢,1¢ = 6.5 Hz, 1 H, 2¢-H), 7.72–
enantiomeric excess (82% ee). A final oxidative demeth-
ylation then afforded (1R,3R)-deoxynanaomycin A (4).
7.76 (m, 2 H, 6-H and 7-H), 8.10–8.17 (m, 2 H, 5-H and 8-H).
13C NMR (75 MHz, CDCl3): d = 35.4 (CH2, C-1¢), 118.3 (CH2, C-
3¢), 127.2 (CH, C-5 or C-8), 127.5 (CH, C-8 or C-5), 131.1 (C, C-
4a or C-8a), 131.4 (CH, C-2¢), 131.5 (C, C-8a or C-4a), 133.9 (CH,
C-7 or C-6), 134.2 (CH, C-6 or C-7), 139.4 (C, C-2 or C-3), 149.0
(C, C-3 or C-2), 177.8 (C, C-1 or C-4), 181.4 (C, C-4 or C-1).
All reactions were carried out in flame- or oven-dried glassware un-
der a dry N2 atmosphere. THF and Et2O were dried over Na wire;
CH2Cl2, pyridine and Et3N were dried over CaH2; EtOH and MeOH
were dried over magnesium ethoxide and methoxide, respectively.
All solvents were distilled prior to use. Flash chromatography was
carried out using 0.063–0.1 mm silica gel with the desired solvent.
TLC was performed using silica-coated aluminum plates (60 F254).
Compounds were identified using UV fluorescence and/or staining
with vanillin in methanolic H2SO4, a solution of ammonium hepta-
molybdate and cerium sulfate in aqueous H2SO4, I2 or a solution of
KMnO4 and K2CO3 in aqueous NaOH. Low-resolution mass spectra
were recorded using a VG-70SE spectrometer operating at a nomi-
nal accelerating voltage of 70 eV. High-resolution mass spectra
were recorded at a nominal resolution of 5000–10000. IR spectra
were obtained using a Perkin–Elmer Spectrum 1000 series FT-IR
spectrometer as a thin film between NaCl plates. NMR spectra were
recorded using either a Bruker DRX300 spectrometer operating at
MS (EI, 70 eV): m/z (%) = 278 (40, M[81Br]+), 276 (40, M[79Br]+),
263 (10), 261 (10), 197 (100, M+ – Br), 169 (20).
HRMS (EI): m/z calcd for C13H981BrO2, C13H979BrO2: 277.9765,
275.9786; found: 277.9772, 275.9787.
2-Allyl-3-bromo-1,4-dimethoxynaphthalene (8)8
To a mixture of 2-allyl-3-bromo-1,4-naphthoquinone (7) (340 mg,
1.23 mmol) and TBAI (46.01 mg, 0.11 mmol) in THF (17 mL) un-
der N2 was added a soln of Na2S2O4 (1.28 g, 7.29 mmol) in H2O (7
mL) with vigorous stirring. After 30 min, KOH (1580 mg, 28.17
mmol) in H2O (7 mL) was added and the mixture was stirred for 1
h followed by the addition of Me2SO4 (2.45 mL, 25.18 mmol). The
mixture was stirred for 4 h then quenched with 1.5 M aq NH3 (8.5
mL) and H2O (250 mL). The crude product was extracted with
EtOAc (3 × 40 mL). The organic extracts were washed with 2 M
HCl (50 mL) and H2O (3 × 60 mL) then dried (anhyd MgSO4). The
solvent was removed under reduced pressure and the crude mixture
was purified by flash chromatography (hexane–EtOAc, 9:1) to yield
compound 8 (361 mg, 1.17 mmol, 95%) as an off-white solid, mp
56–57 °C (lit.8 mp 57 °C).
1
300 MHz for H nuclei and 75 MHz for 13C nuclei or a Bruker
DRX400 spectrometer operating at 400 MHz for 1H nuclei and 100
1
MHz for 13C nuclei. H NMR data are reported as chemical shift,
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet), coupling
constant (J in Hz), relative integral and assignment. Optical rota-
tions were measured using a Perkin–Elmer 341 polarimeter at
l = 589 nm and are given in 10–1 deg cm2 g–1. Melting points were
determined on a Kofler hot-stage apparatus and are uncorrected.
IR (film): 1733, 1577, 1455, 1359, 1265, 1079, 1006 cm–1.
2-Bromo-1,4-naphthoquinone (6)7
1H NMR (300 MHz, CDCl3): d = 3.79 (dt, J1¢,2¢ = 5.8 Hz, J1¢,3¢ = 1.7
Hz, 2 H, 1¢-H), 3.92 (s, 3 H, 4-OMe), 3.98 (s, 3 H, 1-OMe), 5.05 (dd,
To a soln of NBS (14.24 g, 80 mmol) in AcOH (200 mL) and H2O
(400 mL) at 45 °C was added a soln of 1-naphthol (5) (2.90 g, 20
mmol) in AcOH (200 mL) dropwise. The mixture was stirred for 1
h at 45 °C, then cooled to r.t. and H2O (200 mL) was added. The
mixture was extracted with CHCl3 (4 × 100 mL), and the combined
organic layers were washed with sat. NaHCO3 soln (100 mL), H2O
(2 × 100 mL), and brine (100 mL). The organic layer was dried (an-
hyd MgSO4) and the solvent was removed under reduced pressure.
The crude product was purified by flash chromatography (hexane–
EtOAc, 8:2) to afford bromide 6 (4.17 g, 17.6 mmol, 87%) as a
bright yellow solid, mp 132–133 °C (lit.7 mp 131–132 °C).
J
3¢A,2¢ = 18.2 Hz, Jgem = 1.7 Hz, 1 H, 3¢-HA), 5.07 (dd, J3¢B,2¢ = 10.2
Hz, Jgem = 1.7 Hz, 1 H, 3¢-HB), 6.07 (ddt, J2¢,3¢A = 18.2 Hz,
J2¢,3¢B = 10.2 Hz, J2¢,1¢ = 5.8 Hz, 1 H, 2¢-H), 7.25–7.57 (m, 2 H, 6-H
and 7-H), 8.05–8.12 (m, 2 H, 5-H and 8-H).
13C NMR (75 MHz, CDCl3): d = 34.1 (CH2, C-1¢), 61.2 (CH3, 4-
OMe), 61.5 (CH3, 1-OMe), 115.7 (CH2, C-3¢), 116.6 (C, C-2 or C-
3), 122.7 (CH, C-5 or C-8), 122.9 (CH, C-8 or C-5), 126.4 (CH, C-
6 or C-7), 126.4 (CH, C-7 or C-6), 127.9 (C, C-3 or C-2), 128.1 (C,
C-4a or C-8a), 128.8 (C, C-8a or C-4a), 135.6 (CH, C-2¢), 150.0 (C,
C-1 or C-4), 150.8 (C, C-4 or C-1).
MS (EI, 70 eV): m/z (%) = 308 (100, M[81Br]+), 306 (100,
M[79Br]+), 293 (40, M[81Br]+ – Me), 291 (40, M[79Br]+ – Me), 212
(55), 197 (65).
HRMS (EI): m/z calcd for C15H1581BrO2, C15H1579BrO2: 308.0235,
306.0255; found: 308.0238, 306.0261.
IR (film): 1679, 1658, 1590, 1570, 1377, 1246, 1117 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.52 (s, 1 H, 3-H), 7.74–7.82 (m,
2 H, 6-H and 7-H), 8.06–8.11 (m, 1 H, 5-H or 8-H), 8.17–8.21 (m,
1 H, 8-H or 5-H).
HRMS (EI): m/z calcd for C10H579BrO2, C10H581BrO2: 235.9473,
237.9452; found: 235.9474, 237.9457.
2-Allyl-3-bromo-1,4-naphthoquinone (7)8
2-(3-Bromo-1,4-dimethoxynaphthalen-2-yl)ethanal (9)
To a soln of 2-bromo-1,4-naphthoquinone (6) (500 mg, 2.10 mmol)
in MeCN (50 mL) was added AgNO3 (178 mg, 1.05 mmol) and vi-
nylacetic acid (270 mg, 3.15 mmol) then the mixture was heated to
65 °C. To the reaction mixture was added dropwise a soln of
(NH4)2S2O8 (910 mg, 4.0 mmol) in H2O (25 mL) over 30 min and
stirring was continued for 2 h at 65 °C. The mixture was cooled to
r.t. and H2O (50 mL) was added. The mixture was extracted with
EtOAc (3 × 40 mL) and the combined organic layers were washed
with sat. NaHCO3 soln (25 mL), H2O (25 mL) and brine (25 mL),
dried (anhyd MgSO4) and concentrated under reduced pressure. The
crude mixture was purified by flash chromatography (hexane–
EtOAc, 96:4) to yield the allylnaphthoquinone 7 (389 mg, 1.4
mmol, 67%) as a pale orange solid, mp 77–79 °C (lit.8 mp 79 °C).
To a stirred soln of 2-allyl-3-bromo-1,4-dimethoxynaphthalene (8)
(986 mg, 3.21 mmol) in CH2Cl2 (120 mL) under N2 was added 0.1%
Sudan III in CH2Cl2 (3 drops) and the mixture was cooled to –30 °C.
Ozone gas was bubbled into the mixture at –60 °C; the reaction
mixture turned from pink to pale yellow. N2 gas was flushed into the
reaction mixture for 15 min then DMS (3.0 mL, 40.80 mmol) was
added at –60 °C. The mixture was warmed to r.t., and stirring was
continued for 1 h. The solvent was removed under reduced pressure
and the crude mixture was purified by flash chromatography (hex-
ane–EtOAc, 8:2) to yield compound 9 (840 mg, 2.71 mmol, 85%)
as a pale pink solid, mp 68–70 °C.
IR (film): 1724, 1579, 1455, 1359, 1265, 1083, 1006 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.82 (s, 3 H, 4-OMe), 3.95 (s, 3 H,
1-OMe), 4.12 (d, J2¢,1¢ = 1.5 Hz, 2 H, 2¢-H), 7.49–7.54 (m, 2 H, 6-H
and 7-H), 8.01–8.10 (m, 2 H, 5-H and 8-H), 9.84 (t, J1¢,2¢ = 1.5 Hz,
1 H, CHO).
IR (film): 1677, 1665, 1596, 1424, 1277, 1265, 738 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.62 (dt, J1¢,2¢ = 6.5 Hz, J1¢,3¢ = 1.4
Hz, 2 H, 1¢-H), 5.13 (dd, J3¢A,2¢ = 9.6 Hz, Jgem = 1.4 Hz, 1 H, 3¢-HA),
5.25 (dd, J3¢B,2¢ = 17.0 Hz, Jgem = 1.4 Hz, 1 H, 3¢-HB), 5.84 (ddt,
Synthesis 2007, No. 18, 2887–2893 © Thieme Stuttgart · New York

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Enantioselective Synthesis of a Nanaomycin A Analogue
2891
13C NMR (75 MHz, CDCl3): d = 45.0 (CH2, C-2¢), 61.2 (CH3, 4-
OMe), 62.3 (CH3, 1-OMe), 115.7 (C, C-3), 122.5 (CH, C-5 or C-8),
122.5 (CH, C-8 or C-5), 122.8 (C, C-2), 126.8 (CH, C-6 or C-7),
127.0 (CH, C-7 or C-6), 127.5 (C, C-4a or C-8a), 128.6 (C, C-8a or
C-4a), 150.2 (C, C-4 or C-1), 151.7 (C, C-1 or C-4), 198.4 (CHO,
C-1¢).
MS (EI, 70 eV): m/z (%) = 310 (98, M[81Br]+), 308 (100, M[79Br]+),
295 (15, M[81Br]+ – Me), 293 (15, M[79Br]+ – Me), 200 (55), 185
(76).
and the mixture was stirred for 10 min. HClO4 (1 drop) was added
and the resulting violet reaction mixture was stirred for 2 h. The re-
action mixture was quenched with sat. NaHCO3 soln (60 mL) and
extracted with CH2Cl2 (3 × 30 mL). The combined organic layers
were washed with sat. NH4Cl soln (50 mL) and dried (anhyd
Na2SO4). The solvent was removed under reduced pressure and the
crude mixture was purified by flash chromatography (hexane–
EtOAc, 9:1) to yield compound 11 (302 mg, 0.77 mmol, 90%) as a
colorless oil, [a]D +3.0 (c 0.203, CHCl3).
IR (film): 2934, 1739, 1569, 1455, 1359, 1235 cm–1.
HRMS (EI): m/z calcd for C14H1381BrO3, C14H1379BrO3: 310.0028,
308.0048; found: 310.0021, 308.0049.
1H NMR (300 MHz, CDCl3): d = 1.90 (s, 3 H, COCH3), 2.44 (t,
J = 6.5 Hz, 2 H, 3¢-H), 3.22 (dd, Jgem = 13.5 Hz, J1¢A,2¢ = 8.2 Hz, 1 H,
1¢-HA), 3.34 (dd, Jgem = 13.5 Hz, J1¢B,2¢ = 8.2 Hz, 1 H, 1¢-HB), 3.93 (s,
3 H, 4-OMe), 3.96 (s, 3 H, 1-OMe), 5.08 (dd, J5¢A,4¢ = 8.4 Hz,
Jgem = 0.9 Hz, 1 H, 5¢-HA), 5.12 (dd, J5¢B,4¢ = 17.3 Hz, Jgem = 0.7 Hz,
1 H, 5¢-HB), 5.37–5.46 (m, 1 H, 2¢-H), 5.83 (ddt, J4¢,5¢B = 18.0 Hz,
J4¢,5¢A = 8.4 Hz, J4¢,3¢ = 3.2 Hz, 1 H, 4¢-H), 7.49–7.60 (m, 2 H, 6-H
and 7-H), 8.02–8.11 (m, 2 H, 5-H and 8-H).
13C NMR (75 MHz, CDCl3): d = 20.8 (CH3, COCH3), 34.4 (CH2, C-
1¢), 38.5 (CH2, C-3¢), 61.1 (CH3, 4-OMe), 62.0 (CH3, 1-OMe), 72.3
(CH, C-2¢), 116.5 (C, C-3), 117.5 (CH2, C-5¢), 122.4 (CH, C-5 or C-
8), 122.5 (CH, C-8 or C-5), 126.4 (CH, C-6 or C-7), 126.5 (CH, C-
7 or C-6), 126.7 (C, C-2), 127.4 (C, C-4a or C-8a), 128.1 (C, C-8a
or C-4a), 133.6 (CH, C-4¢), 149.9 (C, C-4), 151.5 (C, C-1), 169.9
(C, CO).
(2S)-1-(3-Bromo-1,4-dimethoxynaphthalen-2-yl)-4-penten-2-ol
(10a)
To a stirred suspension of Mg powder (193 mg, 7.95 mmol) in an-
hyd Et2O (10 mL) was added a soln of allyl bromide (389 mg, 3.22
mmol) in anhyd Et2O (5 mL) dropwise under N2. The reaction mix-
ture was heated under reflux for 1 h then cooled to r.t. In another
round-bottom flask, (–)-DIP-Chloride® (1.03 g, 3.22 mmol) was
dissolved in anhyd Et2O (10 mL) and the soln was cooled to 0 °C
under N2. The clear ethereal soln of allylmagnesium bromide was
transferred via cannula into the soln of (–)-DIP-Chloride®. The re-
sulting mixture was stirred for 1 h at r.t., then stirring was discon-
tinued and the magnesium salt was allowed to settle. The clear soln
of B-allyldiisopinocampheylborane (17) was transferred via cannu-
la into another 50-mL round-bottom flask then cooled to –78 °C un-
der N2. A soln of aldehyde 9 (440 mg, 1.42 mmol) in anhyd Et2O
(10 mL) was added dropwise to this cooled soln. After stirring at
–78 °C for 3 h, MeOH (1 mL) and 1 M HCl (1.4 mL) were added
and the reaction mixture was stirred with warming to r.t., then the
mixture was basified (pH = 12) with 2 M NaOH. The mixture was
extracted with CH2Cl2 (3 × 25 mL) and the organic extracts were
dried (anhyd MgSO4). The solvent was removed under reduced
pressure and the crude mixture was purified by flash chromatogra-
phy (toluene–MeCN, 9:1) to yield compound 10a (310 mg, 0.88
mmol, 62%, 82% ee) as a viscous colorless oil, [a]D +21.7 (c 0.260,
CHCl3). The ee was determined by HPLC using a chiral column
(Chiralcel® OD-H, 0.43 cm × 1 cm, Daicel Chemical Industries,
Ltd.) with 2-propanol–hexane (1:99) as eluent (flow rate: 0.5 mL/
min). The retention time (tR) for the major peak was 25 min and the
tR for the minor peak was 33 min.
MS (EI, 70 eV): m/z (%) = 394 (40, M[81Br]+), 392 (40, M[79Br]+),
334 (55, M[81Br]+ – C2H4O2), 332 (55, M[79Br]+ – C2H4O2), 200
(30), 43 (100, M+ – C17H18BrO3).
HRMS (EI): m/z calcd for C19H2181BrO4, C19H2179BrO4: 394.0603,
392.0623; found: 394.0603, 392.0621.
(1R,3S)-3-Allyl-5,10-dimethoxy-1-methyl-3,4-dihydro-1H-
naphtho[2,3-c]pyran (13)
Bromo ester 11 (840 mg, 2.14 mmol) was dissolved in anhyd THF
(50 mL) under a N2 atmosphere and the soln was cooled to –78 °C.
A soln of 1.4 M t-BuLi in pentane (33 mL, 46.2 mmol) was then
added dropwise and the resulting dark red reaction mixture was
stirred for 1 h at the same temperature. The reaction mixture was
quenched with H2O (40 mL) at –78 °C, warmed to r.t., then extract-
ed with EtOAc (3 × 40 mL). The combined organic layers were
washed with brine (20 mL) and dried (anhyd Na2SO4). The solvent
was evaporated to give crude lactol 12 (782 mg), which was used in
the next step without further purification due to its instability on sil-
ica gel. To a soln of the crude lactol 12 (782 mg) in anhyd CH2Cl2
(200 mL) at –78 °C was added TFA (4.9 mL, 64.37 mmol) dropwise
and the mixture was stirred for 15 min. TES (9.8 mL, 64.37 mmol)
was added dropwise to the reaction mixture at –78 °C and the mix-
ture was stirred for 2 h then warmed to r.t. The reaction mixture was
quenched with ice water (50 mL) and extracted with CH2Cl2 (3 × 30
mL). The combined organic extracts were washed with sat. brine
(20 mL) and dried (anhyd Na2SO4). After concentration, the residue
was purified by flash chromatography (hexane–EtOAc, 9:1) to give
compound 13 (498 mg, 1.67 mmol, 78%) as a colorless oil, [a]D
+104.4 (c 0.045, CHCl3).
IR (film): 3444, 1641, 1574, 1455, 1360, 1259, 1083, 914 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.37 (t, J = 5.1 Hz, 2 H, 3¢-H),
2.54 (s, 1 H, OH), 3.17 (d, J1¢,2¢ = 4.8 Hz, 2 H, 1¢-H), 3.86 (s, 3 H, 4-
OMe), 3.91 (s, 3 H, 1-OMe), 4.02–4.09 (m, 1 H, 2¢-H), 5.10 (dd,
J5¢A,4¢ = 9.9 Hz, Jgem = 1.4 Hz, 1 H, 5¢-HA), 5.15 (dd, J5¢B,4¢ = 18.2 Hz,
Jgem = 1.4 Hz, 1 H, 5¢-HB), 5.91 (ddt, J4¢,5¢B = 18.2 Hz, J4¢,5¢A = 9.9
Hz, J4¢,3¢ = 2.3 Hz, 1 H, 4¢-H), 7.43–7.50 (m, 2 H, 6-H and 7-H),
7.97–8.07 (m, 2 H, 5-H and 8-H).
13C NMR (75 MHz, CDCl3): d = 37.6 (CH2, C-1¢), 41.9 (CH2, C-3¢),
61.3 (CH3, 4-OMe), 62.0 (CH3, 1-OMe), 70.7 (CH, C-2¢), 116.5 (C,
C-2 or C-3), 117.8 (CH2, C-5¢), 122.5 (CH, C-5 or C-8), 122.6 (CH,
C-8 or C-5), 126.6 (CH, C-6 or C-7), 126.7 (CH, C-7 or C-6), 127.6
(C, C-3 or C-2), 127.7 (C, C-4a or C-8a), 128.1 (C, C-8a or C-4a),
134.78 (CH, C-4¢), 150.27 (C, C-1 or C-4), 151.19 (C, C-4 or C-1).
MS (EI, 70 eV): m/z (%) = 352 (75, M[81Br]+), 350 (75, M[79Br]+),
282 (84, M[81Br]+ – C4H6O), 280 (84, M[79Br]+ – C4H6O), 267 (95,
M[81Br]+ – C5H9O), 265 (100, M[79Br]+ – C5H9O), 230 (95).
IR (film): 2935, 1591, 1449, 1351, 1091, 1066, 757 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.69 (d, JMe,1 = 6.4 Hz, 3 H, 1-
Me), 2.40–2.47 (m, 1 H, 1¢-HA), 2.50–2.59 (m, 1 H, 1¢-HB), 2.61
(dd, Jgem = 16.1 Hz, J4ax,3 = 11.1 Hz, 1 H, 4-Hax), 3.11 (dd,
Jgem = 16.1 Hz, J4eq,3 = 2.1 Hz, 1 H, 4-Heq), 3.59–3.63 (m, 1 H, 3-H),
3.83 (s, 3 H, 10-OMe), 3.88 (s, 3 H, 5-OMe), 5.13 (dd, J3¢A,2¢ = 10.2
Hz, Jgem = 0.5 Hz, 1 H, 3¢-HA), 5.18 (dd, J3¢B,2¢ = 16.4 Hz, Jgem = 1.0
Hz, 1 H, 3¢-HB), 5.21–5.23 (m, 1 H, 1-H), 5.90–6.04 (m, 1 H, 2¢-H),
7.42–7.48 (m, 2 H, 7-H and 8-H), 8.00–8.08 (m, 2 H, 6-H and 9-H).
HRMS (EI): m/z calcd for C17H1981BrO3, C17H1979BrO3: 352.0497,
350.0518; found: 352.0497, 350.0515.
2-[(2S)-2-Acetoxy-4-penten-1-yl]-3-bromo-1,4-dimethoxynaph-
thalene (11)
To a soln of (S)-homoallylic alcohol 10a (300 mg, 0.85 mmol) in
CH2Cl2 (40 mL) was added dropwise Ac2O (0.96 mL, 10.00 mmol)
Synthesis 2007, No. 18, 2887–2893 © Thieme Stuttgart · New York

2892
M. A. Brimble et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 22.3 (CH3, 1-Me), 29.8 (CH2, C-
4), 40.5 (CH2, C-1¢), 60.9 (CH3, 10-OMe), 61.2 (CH3, 5-OMe), 71.3
(CH, C-1), 73.2 (CH, C-3), 117.0 (CH2, C-3¢), 121.9 (CH, C-6 or C-
9), 122.0 (CH, C-9 or C-6), 124.9 (C, C-4a), 125.5 (CH, C-7 or C-
8), 125.7 (CH, C-8 or C-7), 127.3 (C, C-5a or C-9a), 127.3 (C, C-9a
or C-5a), 129.2 (C, C-10a), 134.5 (CH, C-2¢), 148.3 (C, C-10),
148.9 (C, C-5).
Hz, 1 H, 4-Heq), 3.86 (s, 3 H, 10-OMe), 3.90 (s, 3 H, 5-OMe), 4.09–
4.16 (m, 1 H, 3-H), 5.26 (q, J1,Me = 6.3 Hz, 1 H, 1-H), 7.47–7.51 (m,
2 H, 7-H and 8-H), 8.02–8.08 (m, 2 H, 6-H and 9-H), 9.92 (t,
J1¢,2¢ = 1.0 Hz, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 22.3 (CH3, 1-Me), 30.1 (CH2, C-
4), 49.6 (CH2, C-2¢), 61.1 (CH3, 10-OMe), 61.4 (CH3, 5-OMe), 68.9
(CH, C-1), 71.5 (CH, C-3), 122.0 (CH, C-7 or C-8), 122.2 (CH, C-
8 or C-7), 124.0 (C, C-4a or C-10a), 125.7 (CH, C-6 or C-9), 125.9
(CH, C-9 or C-6), 127.5 (C, C-5a or C-9a), 127.6 (C, C-9a or C-5a),
128.6 (C, C-10a or C-4a), 148.6 (C, C-5 or C-10), 149.1 (C, C-10 or
C-5), 200.9 (CHO, C-1¢).
MS (EI, 70 eV): m/z (%) = 298 (100, M+), 283 (60, M+ – Me), 267
(15, M+ – OMe), 257 (15), 242 (15), 229 (40), 213 (35).
HRMS (EI): m/z calcd for C19H22O3: 298.1569; found: 298.1569.
(1R,2¢R,3R)-3-(2,3-Dihydroxyprop-1-yl)-5,10-dimethoxy-1-
methyl-3,4-dihydro-1H-naphtho[2,3-c]pyran (14a) and
(1R,2¢S,3R)-3-(2,3-Dihydroxyprop-1-yl)-5,10-dimethoxy-1-
methyl-3,4-dihydro-1H-naphtho[2,3-c]pyran (14b)
MS (EI, 70 eV): m/z (%) = 300 (100, M+), 285 (80, M+ – Me), 269
(20, M+ – OMe), 241 (10), 227 (10), 225 (10).
HRMS (EI): m/z calcd for C18H20O4: 300.1362; found: 300.1360.
To a soln of cyclic ether 13 (286 mg, 0.95 mmol) in acetone (30 mL)
and H2O (6 mL) was added NMO (155.8 mg, 1.33 mmol) and the
mixture was cooled to 0 °C. After 5 min, OsO4 (0.11 mL, 0.01
mmol, 2.5 wt% soln) was added and the soln was gradually warmed
to r.t. The reaction mixture was stirred for 24 h, then 33% aq
Na2SO3 (5 mL) was added and the mixture was extracted with
EtOAc (3 × 30 mL). The combined organic layers were washed
with H2O (30 mL) and brine (30 mL). After drying (anhyd Na2SO4),
the solvent was removed under reduced pressure and the crude
product was purified by flash chromatography (hexane–EtOAc,
1:1) to yield compounds 14a,b (286 mg, 0.86 mmol, 90%) in a 1:1
ratio as a colorless oil.
2-[(1R,3R)-5,10-Dimethoxy-1-methyl-3,4-dihydro-1H-naph-
tho[2,3-c]pyran-3-yl]acetic Acid (16)
To a soln of aldehyde 15 (25 mg, 0.08 mmol) in t-BuOH (2.5 mL)
was added H2O (0.5 mL) and cyclohexene (1 mL), and the mixture
was stirred for 5 min. NaClO2 (37 mg, 0.41 mmol) and
NaH2PO4·H2O (57 mg, 0.42 mmol) were then added and the mix-
ture was stirred for 1.5 h at r.t. The reaction mixture was cooled to
0 °C, NaHSO3 powder (28 mg, 0.26 mmol) was added and the mix-
ture was diluted with sat. Na3PO4 soln (10 mL). The mixture was
extracted with EtOAc (3 × 15 mL) and the combined organic layers
were washed with brine (15 mL) then dried (anhyd Na2SO4). The
solvent was removed under reduced pressure and the residue was
purified by flash chromatography (hexane–EtOAc, 5:5) to yield
compound 16 (18 mg, 0.057 mmol, 68%, 82% ee) as a colorless oil,
[a]D +59.4 (c 0.069, CHCl3). The ee was determined by HPLC using
a chiral column (Chiralcel® AD-H, 0.46 cm × 25 cm, Diacel Chem-
ical Industries, Ltd.) with 2-propanol–hexane (5:95) as eluent (flow
rate: 0.4 mL/min). The tR for the minor peak was 36 min and the tR
for the major peak was 44 min.
IR (film): 3430, 1640, 1592, 1455, 1353, 1215, 1068 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.68 (d, JMe,1 = 6.3 Hz, 3 H, 1-
Me), 1.83–1.88 (m, 1 H, 1¢-HA), 1.93–1.99 (m, 1 H, 1¢-HB), 2.68–
2.81 (m, 1 H, 4-HA), 2.87 (s, 1 H, OH), 3.03–3.12 (m, 1 H, 4-HB),
3.31 (s, 1 H, OH), 3.56–3.63 (m, 1 H, 3¢-HA), 3.68–3.79 (m, 1 H, 3¢-
HB), 3.70 (s, 3 H, 5-OMe), 3.86 (s, 3 H, 10-OMe), 3.85–3.89 (m, 1
H, 2¢-H), 4.02–4.14 (m, 1 H, 3-H), 5.29–5.32 (m, 1 H, 1-H), 7.26–
7.49 (m, 2 H, 7-H and 8-H), 8.02–8.07 (m, 2 H, 6-H and 9-H).
IR (film): 3054, 1737, 1715, 1662, 1421, 1353, 1265, 1061 cm–1.
13C NMR (75 MHz, CDCl3): d = 22.4, 22.5 (CH3, 1-Me), 30.1, 30.6
(CH2, C-4), 38.5, 38.7 (CH2, C-1¢), 61.0, 61.1 (CH3, 5-OMe), 61.3
(CH3, 10-OMe), 66.6, 66.9 (CH2, C-3¢), 69.5, 71.1 (CH, C-3), 71.4,
71.6 (CH, C-1), 71.8, 73.9 (CH, C-2¢), 122.0, 122.1 (CH, C-6 or C-
9), 124.0 (C, C-10a or C-4a), 124.5 (C, C-4a or C-10a), 125.6, 125.7
(CH, C-9 or C-6), 125.8, 125.9 (CH, C-7 or C-8), 127.4, 127.6 (CH,
C-8 or C-7), 128.2 (C, C-5a or C-9a), 128.5 (C, C-9a or C-5a), 148.5
(C, C-5 or C-10), 148.9, 149.0 (C, C-10 or C-5).
1H NMR (400 MHz, CDCl3): d = 1.69 (d, JMe,1 = 6.4 Hz, 3 H, 1-
Me), 2.68–2.86 (m, 3 H, 4-Hax, 2¢-HA and 2¢-HB), 3.19 (dd,
Jgem = 15.9 Hz, J4eq,3 = 1.9 Hz, 1 H, 4-Heq), 3.87 (s, 3 H, 10-OMe),
3.91 (s, 3 H, 5-OMe), 4.03–4.10 (m, 1 H, 3-H), 5.28 (q, J1,Me = 6.4
Hz, 1 H, 1-H), 7.46–7.51 (m, 2 H, 7-H and 8-H), 8.02–8.08 (m, 2 H,
6-H and 9-H).
13C NMR (75 MHz, CDCl3): d = 22.3 (CH3, 1-Me), 29.8 (CH2, C-
4), 40.9 (CH2, C-2¢), 61.1 (CH3, 10-OMe), 61.4 (CH3, 5-OMe), 70.0
(CH, C-3), 71.7 (CH, C-1), 122.0 (CH, C-7 or C-8), 122.1 (CH, C-
8 or C-7), 123.9 (C, C-4a), 125.7 (CH, C-6 or C-9), 125.9 (CH, C-9
or C-6), 127.5 (C, C-5a or C-9a), 127.6 (C, C-9a or C-5a), 128.5 (C,
C-10a), 148.6 (C, C-10), 149.1 (C, C-5), 176.0 (CO2H, C-1¢).
MS (EI, 70 eV): m/z (%) = 332 (100, M+), 317 (30), 299 (30), 228
(45), 213 (45).
HRMS (EI): m/z calcd for C19H24O5: 332.1624; found: 332.1623.
2-[(1R,3R)-5,10-Dimethoxy-1-methyl-3,4-dihydro-1H-naph-
tho[2,3-c]pyran-3-yl]ethanal (15)
MS (EI, 70 eV): m/z (%) = 316 (90, M+), 301 (100, M+ – Me), 285
(17, M+ – OMe), 267 (20), 255 (25), 241 (10).
Diols 14a,b (52 mg, 0.15 mmol) were dissolved in MeOH (6 mL)
and H2O (2 mL) and the soln was cooled to 0 °C. NaIO4 (38 mg,
0.18 mmol) was added in several portions at 0 °C and the mixture
was stirred for 2 h at the same temperature. Once the reaction was
complete, the reaction mixture was warmed to r.t. then extracted
with Et2O (3 × 15 mL). The combined extracts were washed with
brine (20 mL) and dried (anhyd Na2SO4). The solvent was removed
under reduced pressure and the residue was purified by flash chro-
matography (hexane–EtOAc, 1:1) to yield compound 15 (38 mg,
0.127 mmol, 81%) as an off-white solid, [a]D +85.4 (c 0.048,
CHCl3), mp 107–110 °C.
HRMS (EI): m/z calcd for C18H20O5: 316.1311; found: 316.1309.
2-[(1R,3R)-1-Methyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naph-
tho[2,3-c]pyran-3-yl]acetic Acid (4)
A soln of dimethoxynaphthalene 16 (18 mg, 0.06 mmol) in MeCN
(5 mL) was cooled to 0 °C. To this soln was added dropwise with
stirring a soln of CAN (94 mg, 0.17 mmol) in H2O (5 mL). The re-
action mixture was poured into H2O (20 mL) and extracted with
EtOAc (3 × 15 mL). The combined organic layers were washed
with brine (15 mL), dried (anhyd Na2SO4) and concentrated. The
crude mixture was purified by flash chromatography (hexane–
EtOAc, 1:1) to afford compound 4 (12 mg, 0.042 mmol, 74%) as a
pale yellow solid, [a]D +148.8 (c 0.031, CHCl3), mp 124–126 °C.
IR (film): 2018, 1762, 1725, 1352, 1215, 1067, 1012 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.67 (d, JMe,1 = 6.3 Hz, 3 H, 1-
Me), 2.68–2.76 (m, 2 H, 2¢-H), 2.87 (ddd, Jgem = 16.6 Hz, J4ax,3 = 8.0
Hz, J4ax,1 = 2.3 Hz, 1 H, 4-Hax), 3.15 (dd, Jgem = 16.6 Hz, J4eq,3 = 1.9
IR (film): 3054, 2100, 1715, 1661, 1295, 1215, 755 cm–1.
Synthesis 2007, No. 18, 2887–2893 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of a Nanaomycin A Analogue
2893
1H NMR (300 MHz, CDCl3): d = 1.54 (d, JMe,1 = 6.6 Hz, 3 H, 1-
Me), 2.36 (ddd, Jgem = 18.4 Hz, J4ax,3 = 10.4 Hz, J4ax,1 = 3.8 Hz, 1 H,
4-Hax), 2.65–2.81 (m, 2 H, 2¢-H), 2.90 (dd, Jgem = 18.3 Hz,
J4eq,3 = 2.6 Hz, 1 H, 4-Heq), 3.90–3.99 (m, 1 H, 3-H), 4.85–4.94 (m,
1 H, 1-H), 7.68–7.74 (m, 2 H, 6-H and 9-H), 8.01–8.11 (m, 2 H, 7-
H and 8-H).
13C NMR (75 MHz, CDCl3): d = 20.7 (CH3, 1-Me), 28.3 (CH2, C-
4), 40.2 (CH2, C-2¢), 69.0 (CH, C-3), 70.3 (CH, C-1), 126.3 (CH, C-
6 or C-9), 126.3 (CH, C-9 or C-6), 131.7 (C, C-5a or C-9a), 132.4
(C, C-9a or C-5a), 133.7 (CH, C-7 or C-8), 133.8 (CH, C-8 or C-7),
141.7 (C, C-4a), 146.5 (C, C-10a), 175.3 (CO2H, C-1¢), 183.6 (C, C-
10 or C-5), 183.7 (C, C-5 or C-10).
(14) Gauthier, D. R.; Carreira, E. M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2363.
(15) (a) Keck, G. E.; Krishnamurthy, D. K. Org. Synth. Coll. Vol.
X; Wiley & Sons: New York, 2004, 632. (b) Keck, G. E.;
Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115,
8467. (c) Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993,
34, 7827.
(16) (a) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56,
401. (b) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown,
H. C. J. Org. Chem. 1986, 51, 432. (c) Reddy, M. V. R.;
Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem.
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MS (EI, 70 eV): m/z (%) = 286 (90, M+), 268 (40, M+ – H2O), 240
(35), 226 (100), 223 (10), 213 (20), 211 (40).
HRMS (EI): m/z calcd for C16H14O5: 286.0841; found: 286.0842.
(17) Felpin, F.-X.; Bertrand, M.-J.; Lebreton, J. Tetrahedron
Acknowledgments
2002, 58, 7381.
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The authors thank the Department of Chemistry, University of
Auckland, New Zealand for the award of a Departmental Scholar-
ship (P.B.) for this work.
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Synthesis 2007, No. 18, 2887–2893 © Thieme Stuttgart · New York